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1
Hansbro, Philip, Emma Beckett, Richard Stevens, Andrew Jarnicki, Richard Kim, Irwan Hanish, Nicole Hansbro, et al. "A short-term model of COPD identifies a role for mast cell tryptase (P3242)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 136.3. http://dx.doi.org/10.4049/jimmunol.190.supp.136.3.
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Abstract Cigarette smoke-induced chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory disorder of the lung. The development of effective therapies for COPD has been hampered by the lack of an animal model that mimics the human disease in a short time-frame.We have created a mouse model of cigarette smoke-induced COPD that develops the hallmark features of the human condition in a short amount of time. Tightly controlled amounts of cigarette smoke were delivered to the airways of mice, and the development of the pathological features of COPD were assessed. The roles of macrophages and mast cell (MC) tryptase in pathogenesis were evaluated using depletion and in vitro studies and MC protease-6 deficient mice. After 8 weeks of smoke exposure, wild-type mice developed chronic inflammation, mucus hypersecretion, airway remodeling, emphysema, and reduced lung function. These characteristic features of COPD were glucocorticoid-resistant and did not spontaneously resolve. Systemic effects on skeletal muscle and the heart, and increased susceptibility to respiratory infections also were observed. We demonstrate here that macrophages and tryptase-expressing MCs were required for the development of COPD. Recombinant MC tryptase induced pro-inflammatory responses from cultured macrophages. This model can be used to better understand multiple aspects of COPD pathogenesis.
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Hansbro, Philip, Tatt Haw, Prema Nair, Irwan Hanish, Duc Nguyen, Gang Liu, Mark Inman, et al. "Tumour necrosis factor-related apoptosis inducing ligand promotes the development of experimental chronic obstructive pulmonary disease (MUC1P.905)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 64.6. http://dx.doi.org/10.4049/jimmunol.194.supp.64.6.
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Abstract Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and causes significant healthcare and economic burden. Cigarette smoking is a major risk factor. There is a lack of effective treatments for COPD due to the poor understanding of the underlining mechanisms. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is implicated in respiratory diseases such as asthma and pulmonary fibrosis. However, the role of TRAIL in the pathogenesis of COPD is unknown. In this study, TRAIL mRNA expression and/or protein levels in the lung (airway and parenchyma) and serum were increased in a mouse model of cigarette smoke-induced experimental COPD. Genetic deletion of TRAIL significantly reduced cigarette smoke-induced pulmonary inflammation, expression of key pro-inflammatory mediators, emphysema-like alveolar enlargement and improved lung function in experimental COPD. Interestingly, genetic deletion of TRAIL led to spontaneous small airway remodelling characterized by increased airway epithelial cell thickness and collagen deposition. Importantly, antibody-mediated neutralization of TRAIL reduced cigarette smoke-induced pulmonary inflammation, emphysema-like alveolar enlargement and small airway remodelling. Our study is the first to show that TRAIL plays an important role in the pathogenesis of COPD and provides further evidence for TRAIL being a pivotal inflammatory cytokine in respiratory diseases.
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Kang, Jee Hyun, Yu-Jin Kim, Eun Bok Baek, Eun-Ju Hong, Mee-Young Lee, and Hyo-Jung Kwun. "Anti-Inflammatory and Anti-Airway Remodeling Activities of Jakyakgamcho-Tang in a Mouse Model of COPD." Applied Sciences 12, no. 17 (August 29, 2022): 8646. http://dx.doi.org/10.3390/app12178646.
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Jakyakgamcho-tang (JGT) is used in oriental medicine to treat inflammation and allergy. Chronic obstructive pulmonary disease (COPD) causes respiratory inflammation, airway remodeling, and pulmonary emphysema. We examine the influence of JGT on COPD by using a mouse model. COPD was induced by inhalation of cigarette smoke (CS) and nasal administration of lipopolysaccharide (LPS). In comparison to COPD mice induced by CS and LPS, mice administered with JGT exhibited significantly lower amounts of inflammatory cells and reduced expression levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and monocyte chemoattractant protein-1 (MCP-1) in bronchoalveolar lavage fluid (BALF) and lung tissue. The elevated concentrations of transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA), and matrix metallopeptidase-9 (MMP-9) induced by CS and LPS were also inhibited by JGT treatment. Moreover, JGT suppressed CS and LPS-induced phosphorylation of nuclear factor kappa B (NF-κB), extracellular signal-regulated kinase1/2 (ERK1/2) and mitogen-activated protein kinases (p38 MAPKs). In a COPD mouse model, our results demonstrated that JGT prevented CS and LPS induced airway inflammation and remodeling.
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Zhou, Jie-Sen, Zhou-Yang Li, Xu-Chen Xu, Yun Zhao, Yong Wang, Hai-Pin Chen, Min Zhang, et al. "Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice." European Respiratory Journal 56, no. 3 (May 4, 2020): 2000404. http://dx.doi.org/10.1183/13993003.00404-2020.
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It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1−/−, Mmp12−/−, and Il17a−/− mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1−/−mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.
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Norton, K., M. Freke, S. Groom, and S. Mason. "ALTERED GENE EXPRESSION AND AIRWAY REMODELING IN TWO CIGARETTE SMOKE MODELS OF COPD IN THE MOUSE." Journal of Pharmacological and Toxicological Methods 56, no. 2 (September 2007): e60. http://dx.doi.org/10.1016/j.vascn.2007.02.120.
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Rho, Jinhyung, Chang-Seob Seo, Eun-Ju Hong, Eun Bok Baek, Eunhye Jung, Suyoung Park, Mee-Young Lee, and Hyo-Jung Kwun. "Yijin-Tang Attenuates Cigarette Smoke and Lipopolysaccharide-Induced Chronic Obstructive Pulmonary Disease in Mice." Evidence-Based Complementary and Alternative Medicine 2022 (January 5, 2022): 1–12. http://dx.doi.org/10.1155/2022/7902920.
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Background. Chronic obstructive pulmonary disease (COPD) refers to a lung disorder associated with symptoms of dyspnea, cough, and sputum production. Traditionally, Yijin-tang (YJT), a mixture of Pinellia ternate, Poria cocos, ginger, Chinese liquorice, and tangerine peel, has been prescribed for the treatment of respiratory system diseases caused by dampness phlegm. This experiment investigated the therapeutic effect of YJT in a mouse model of cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced COPD. Methods. COPD was induced by exposing mice to CS for 1 hour per day for 8 weeks, with intranasal delivery of LPS on weeks 1, 3, 5, and 7. YJT was administered at doses of 100 and 200 mg/kg 1 hour before CS exposure for the last 4 weeks. Results. YJT significantly suppressed CS- and LPS-induced increases in inflammatory cell counts and reduced interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) levels in bronchoalveolar lavage fluid (BALF) and lung tissue. In addition, YJT not only decreased airway wall thickness, average alveolar intercept, and lung fibrosis, but it also suppressed the expression of matrix metallopeptidase (MMP)-7, MMP-9, and transforming growth factor-B (TGF-β) and collagen deposition. Moreover, YJT suppressed phosphorylation of nuclear factor-kappa B (NF-κB) as well as expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Conclusion. Collectively, our findings show that YJT attenuates respiratory inflammation and airway remodeling caused by CS and LPS exposure; therefore, therapeutic applications in COPD can be considered.
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Hao, Binwei, Ruiting Sun, Xiaotong Guo, Lili Zhang, Jieda Cui, Yumin Zhou, Wei Hong, et al. "NOX4-Derived ROS Promotes Collagen I Deposition in Bronchial Smooth Muscle Cells by Activating Noncanonical p38MAPK/Akt-Mediated TGF-β Signaling." Oxidative Medicine and Cellular Longevity 2021 (March 19, 2021): 1–20. http://dx.doi.org/10.1155/2021/6668971.
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Background. Airway smooth muscle (ASM) remodeling is a hallmark in chronic obstructive pulmonary disease (COPD). NADPH oxidase 4- (NOX4-) mediated reactive oxygen species (ROS) production plays a crucial role in cell differentiation and extracellular matrix (ECM) synthesis in ASM remodeling. However, the precise mechanisms underpinning its pathogenic roles remain elusive. Methods. The expression of NOX4 and TGF-β1 in the airway of the lung was measured in COPD patients and the control group. Cigarette smoke- (CS-) induced emphysema mice were generated, and the alteration of α-SMA, NOX4, TGF-β1, and collagen I was accessed. The changes of the expression of ECM markers, NOX4, components of TGF-β/Smad, and MAPK/Akt signaling in human bronchial smooth muscle cells (HBSMCs) were ascertained for delineating mechanisms of NOX4-mediated ROS production on cell differentiation and remodeling in human ASM cells. Results. An increased abundance of NOX4 and TGF-β1 proteins in the epithelial cells and ASM of lung was observed in COPD patients compared with the control group. Additionally, an increased abundance expression of NOX4 and α-SMA was observed in the lungs of the CS-induced emphysema mouse model. TGF-β1 displayed abilities to increase the oxidative burden and collagen I production, along with enhanced phosphorylation of ERK, p38MAPK, and p-Akt473 in HBSMCs. These effects of TGF-β1 could be inhibited by the ROS scavenger N-acetylcysteine (NAC), siRNA-mediated knockdown of Smad3 and NOX4, and pharmacological inhibitors SB203580 (p38MAPK inhibitor) and LY294002 (Akt inhibitor). Conclusions. NOX4-mediated ROS production alters TGF-β1-induced cell differentiation and collagen I protein synthesis in HBSMCs in part through the p38MAPK/Akt signaling pathway in a Smad-dependent manner.
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Kang, Jee Hyun, Eunhye Jung, Eun-Ju Hong, Eun Bok Baek, Mee-Young Lee, and Hyo-Jung Kwun. "Effects of Cheonwangbosim-dan in a Mouse Model of Chronic Obstructive Pulmonary Disease: Anti-Inflammatory and Anti-Fibrotic Therapy." Applied Sciences 13, no. 3 (January 31, 2023): 1829. http://dx.doi.org/10.3390/app13031829.
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Chronic obstructive pulmonary disease (COPD) is a lung illness, marked by dyspnea, coughing, and sputum production. Cheonwangbosim-dan (CBD) is a traditional East Asian medicine, consisting of a combination of 15 medicinal herbs, which is frequently used to treat arterial/auricular flutter, neuroses, cardiac-malfunction-induced diseases, and insomnia. The present study evaluated the therapeutic effect of CBD (100 or 200 mg/kg) on COPD using a mouse model of COPD induced by cigarette smoke (CS) and lipopolysaccharide (LPS). The increase in inflammatory cell numbers caused by exposure to CS and LPS was significantly reduced by CBD administration. In addition, CBD therapy reduced interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid (BALF). In lung tissue, CBD not only reduced the levels of IL-1β (CBD 100: p < 0.001 and CBD 200: p < 0.001), IL-6 (CBD 100: p < 0.001 and CBD 200: p < 0.001), TNF-α (CBD 100: p = 0.005 and CBD 200: p = 0.014), and monocyte chemoattractant protein-1 (MCP-1; CBD 100: p = 0.018 and CBD 200: p = 0.003), but also decreased the expression of α-smooth muscle actin (α-SMA; CBD 100: p < 0.001 and CBD 200: p < 0.001), transforming growth factor-β (TGF-β; CBD 100: p < 0.001 and CBD 200: p < 0.001), matrix metallopeptidase-7 (MMP-7; CBD 100: p = 0.019 and CBD 200: p < 0.001), MMP-9 (CBD 100: p = 0.015 and CBD 200: p = 0.013), and tissue inhibitor of metalloproteinase-1 (TIMP-1; CBD 100: p = 0.035 and CBD 200: p = 0.013) compared with the COPD group. CBD was also found to suppress the phosphorylation of nuclear factor kappa B (NF-κB), extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 mitogen-activated protein kinases (p38 MAPK). Taken together, these findings showed that CBD can attenuate respiratory inflammation and airway remodeling induced by exposure to CS and LPS, suggesting that CBD has probable preventive and therapeutic applications in patients with COPD.
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Wang, Liang, Jing Meng, Caicai Wang, Chao Yang, Yuan Wang, Yamei Li, and Yujing Li. "Hydrogen sulfide alleviates cigarette smoke-induced COPD through inhibition of the TGF-β1/smad pathway." Experimental Biology and Medicine 245, no. 3 (February 2020): 190–200. http://dx.doi.org/10.1177/1535370220904342.
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Smoking has become a major cause of chronic obstructive pulmonary disease through weakening of the respiratory mucus-ciliary transport system, impairing cough reflex sensitivity, and inducing inflammation. Recent researches have indicated that hydrogen sulfide is essential in the development of various lung diseases. However, the effect and mechanism of hydrogen sulfide on cigarette smoke-induced chronic obstructive pulmonary disease have not been reported. In this study, rats were treated with cigarette smoke to create a chronic obstructive pulmonary disease model followed by treatment with a low concentration of hydrogen sulfide. Pulmonary function, histopathological appearance, lung edema, permeability, airway remodeling indicators, oxidative products/antioxidases levels, inflammatory factors in lung, cell classification in bronchoalveolar lavage fluid were measured to examine the effect of hydrogen sulfide on chronic obstructive pulmonary disease model. The results showed that hydrogen sulfide effectively improved pulmonary function and reduced histopathological changes, lung edema, and permeability. Airway remodeling, oxidative stress, and inflammation were also reduced by hydrogen sulfide treatment. To understand the mechanisms, we measured the expression of TGF-β1, TGF-βIand TGF-βII receptors and Smad7 and phosphorylation of Smad2/Smad3. The results indicated that the TGF-β1 and Smad were activated in cigarette smoke-induced chronic obstructive pulmonary disease model, but inhibited by hydrogen sulfide. In conclusion, this study showed that hydrogen sulfide treatment alleviated cigarette smoke-induced chronic obstructive pulmonary disease through inhibition of the TGF-β1/Smad pathway. Impact statement COPD has become a severe public health issue in the world and smoking has become a major cause of COPD. As a result, it is a demandingly needed to explore new potential therapy for cigarette smoke-associated COPD. The present study suggested that H2S treatment improved pulmonary function and reduced histopathological changes, lung edema, permeability, inflammation, airway remodeling and oxidative injury in a COPD model induced by cigarette smoke. Although additional studies are required to elucidate the pharmacodynamics, pharmacokinetics, and pharmacology of H2S in the cigarette smoke-associated COPD, our findings provide an experimental basis for the potential clinical application of H2S in COPD treatment.
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Churg, Andrew, Manuel Cosio, and Joanne L. Wright. "Mechanisms of cigarette smoke-induced COPD: insights from animal models." American Journal of Physiology-Lung Cellular and Molecular Physiology 294, no. 4 (April 2008): L612—L631. http://dx.doi.org/10.1152/ajplung.00390.2007.
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Cigarette smoke-induced animal models of chronic obstructive pulmonary disease support the protease-antiprotease hypothesis of emphysema, although which cells and proteases are the crucial actors remains controversial. Inhibition of either serine or metalloproteases produces significant protection against emphysema, but inhibition is invariably accompanied by decreases in the inflammatory response to cigarette smoke, suggesting that these inhibitors do more than just prevent matrix degradation. Direct anti-inflammatory interventions are also effective against the development of emphysema, as are antioxidant strategies; the latter again decrease smoke-induced inflammation. There is increasing evidence for autoimmunity, perhaps directed against matrix components, as a driving force in emphysema. There is intriguing but controversial animal model evidence that failure to repair/failure of lung maintenance also plays a role in the pathogenesis of emphysema. Cigarette smoke produces small airway remodeling in laboratory animals, possibly by direct induction of fibrogenic growth factors in the airway wall, and also produces pulmonary hypertension, at least in part through direct upregulation of vasoactive mediators in the intrapulmonary arteries. Smoke exposure causes goblet cell metaplasia and excess mucus production in the small airways and proximal trachea, but these changes are not good models of either chronic bronchitis or acute exacerbations. Emphysema, small airway remodeling, pulmonary hypertension, and mucus production appear to be at least partially independent processes that may require different therapeutic approaches.
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Stanford, Denise, Harrison Kim, Sandeep Bodduluri, Jennifer LaFontaine, Stephen A. Byzek, Trenton R. Schoeb, Elex S. Harris, et al. "Airway remodeling in ferrets with cigarette smoke-induced COPD using µCT imaging." American Journal of Physiology-Lung Cellular and Molecular Physiology 319, no. 1 (July 1, 2020): L11—L20. http://dx.doi.org/10.1152/ajplung.00328.2019.
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Structural changes to airway morphology, such as increased bronchial wall thickness (BWT) and airway wall area, are cardinal features of chronic obstructive pulmonary disease (COPD). Ferrets are a recently established animal model uniquely exhibiting similar clinical and pathological characteristics of COPD as humans, including chronic bronchitis. Our objective was to develop a microcomputed tomography (µCT) method for evaluating structural changes to the airways in ferrets and assess whether the effects of smoking induce changes consistent with chronic bronchitis in humans. Ferrets were exposed to mainstream cigarette smoke or air control twice daily for 6 mo. µCT was conducted in vivo at 6 mo; a longitudinal cohort was imaged monthly. Manual measurements of BWT, luminal diameter (LD), and BWT-to-LD ratio (BWT/LD) were conducted and confirmed by a semiautomated algorithm. The square root of bronchial wall area (√WA) versus luminal perimeter was determined on an individual ferret basis. Smoke-exposed ferrets reproducibly demonstrated 34% increased BWT ( P < 0.001) along with increased LD and BWT/LD versus air controls. Regression indicated that the effect of smoking on BWT persisted despite controlling for covariates. Semiautomated measurements replicated findings. √WA for the theoretical median airway luminal perimeter of 4 mm (Pi4) was elevated 4.4% in smoke-exposed ferrets ( P = 0.015). Increased BWT and Pi4 developed steadily over time. µCT-based airway measurements in ferrets are feasible and reproducible. Smoke-exposed ferrets develop increased BWT and Pi4, changes similar to humans with chronic bronchitis. µCT can be used as a significant translational platform to measure dynamic airway morphological changes.
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Singanayagam, Aran, and Sebastian L. Johnston. "Smoke and viruses–a hindrance to relaxing the airways?" Clinical Science 130, no. 10 (April 19, 2016): 839–41. http://dx.doi.org/10.1042/cs20160139.
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Inhaled β2-adrenoceptor agonists are a mainstay of therapy for airways diseases and are almost universally prescribed for patients with asthma or chronic obstructive pulmonary disease (COPD). Very few studies have evaluated the efficacy of these commonly used therapies during acute disease exacerbations which are frequently triggered by viral infection. In this edition of Clinical Science, Donovan et al. assess the ex vivo effects of the most commonly used short-acting β2-agonist salbutamol on small airway reactivity using precision cut lung slices (PCLS) from a mouse model of virus-induced exacerbation of COPD. They demonstrate that combined challenge with cigarette smoke and influenza infection in mice markedly impairs salbutamol-mediated airway relaxation. The findings of the present study suggest that cigarette smoke and respiratory virus infection may intefere with the ability of commonly prescribed therapies to effectively bronchodilate the airways.
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Eurlings, Irene M. J., Mieke A. Dentener, Evi M. Mercken, Rafael de Cabo, Ken R. Bracke, Juanita H. J. Vernooy, Emiel F. M. Wouters, and Niki L. Reynaert. "A comparative study of matrix remodeling in chronic models for COPD; mechanistic insights into the role of TNF-α." American Journal of Physiology-Lung Cellular and Molecular Physiology 307, no. 7 (October 1, 2014): L557—L565. http://dx.doi.org/10.1152/ajplung.00116.2014.
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Remodeling in chronic obstructive pulmonary disease (COPD) has at least two dimensions: small airway wall thickening and destruction of alveolar walls. Recently we showed comparable alterations of the extracellular matrix (ECM) compounds collagen, hyaluoran, and elastin in alveolar and small airway walls of COPD patients. The aim of this study was to characterize and assess similarities in alveolar and small airway wall matrix remodeling in chronic COPD models. From this comparative characterization of matrix remodeling we derived and elaborated underlying mechanisms to the matrix changes reported in COPD. Lung tissue sections of chronic models for COPD, either induced by exposure to cigarette smoke, chronic intratracheal lipopolysaccharide instillation, or local tumor necrosis factor (TNF) expression [surfactant protein C (SPC)-TNFα mice], were stained for elastin, collagen, and hyaluronan. Furthermore TNF-α matrix metalloproteinase (MMP)-2, -9, and -12 mRNA expression was analyzed using qPCR and localized using immunohistochemistry. Both collagen and hyaluronan were increased in alveolar and small airway walls of all three models. Interestingly, elastin contents were differentially affected, with a decrease in both alveolar and airway walls in SPC-TNFα mice. Furthermore TNF-α and MMP-2 and -9 mRNA and protein levels were found to be increased in alveolar walls and around airway walls only in SPC-TNFα mice. We show that only SPC-TNFα mice show changes in elastin remodeling that are comparable to what has been observed in COPD patients. This reveals that the SPC-TNFα model is a suitable model to study processes underlying matrix remodeling and in particular elastin breakdown as seen in COPD. Furthermore we indicate a possible role for MMP-2 and MMP-9 in the breakdown of elastin in airways and alveoli of SPC-TNFα mice.
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Wang, Ting, Xiaohui Du, Zhihua Wang, Yiya Gu, Qian Huang, Jixing Wu, Yuan Zhan, Jinkun Chen, Chengfeng Xiao, and Jungang Xie. "p55PIK deficiency and its NH2-terminal derivative inhibit inflammation and emphysema in COPD mouse model." American Journal of Physiology-Lung Cellular and Molecular Physiology 321, no. 1 (July 1, 2021): L159—L173. http://dx.doi.org/10.1152/ajplung.00560.2020.
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Chronic obstructive pulmonary disease (COPD) is composed of chronic airway inflammation and emphysema. Recent studies show that Class IA phosphatidylinositol 3-kinases (PI3Ks) play an important role in the regulation of inflammation and emphysema. However, there are few studies on their regulatory subunits. p55PIK is a regulatory subunit of Class IA PI3Ks, and its unique NH2-terminal gives it special functions. p55PIK expression in the lungs of nonsmokers, smokers, and patients with COPD was examined. We established a fusion protein TAT-N15 from the NH2-terminal effector sequence of p55PIK and TAT (the transduction domain of HIV transactivator protein) and investigated the effects of silencing p55PIK or adding TAT-N15 on cigarette smoke exposure at the cellular and animal level. p55PIK expression was increased in patients with COPD. p55PIK deficiency and TAT-N15 significantly inhibited the cigarette smoke extract-induced IL-6, IL-8, and activation of the Akt and the NF-κB pathway in BEAS-2B. p55PIK deficiency and TAT-N15 intranasal administration prevented emphysema and the lung function decline in mice exposed to smoke for 6 mo. p55PIK deficiency and TAT-N15 significantly inhibited lung inflammatory infiltration, reduced levels of IL-6 and KC in mice lung homogenate, and inhibited activation of the Akt and the NF-κB signaling in COPD mice lungs. Our studies indicate that p55PIK is involved in the pathogenesis of COPD, and its NH2-terminal derivative TAT-N15 could be an effective drug in the treatment of COPD by inhibiting the activation of the Akt and the NF-κB pathway.
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Pouwels, Simon D., Alen Faiz, Lisette E. den Boef, Reneé Gras, Maarten van den Berge, H. Marike Boezen, Ron Korstanje, et al. "Genetic variance is associated with susceptibility for cigarette smoke-induced DAMP release in mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 313, no. 3 (September 1, 2017): L559—L580. http://dx.doi.org/10.1152/ajplung.00466.2016.
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Chronic obstructive pulmonary disease (COPD) is characterized by unresolved neutrophilic airway inflammation and is caused by chronic exposure to toxic gases, such as cigarette smoke (CS), in genetically susceptible individuals. Recent data indicate a role for damage-associated molecular patterns (DAMPs) in COPD. Here, we investigated the genetics of CS-induced DAMP release in 28 inbred mouse strains. Subsequently, in lung tissue from a subset of strains, the expression of the identified candidate genes was analyzed. We tested whether small interfering RNA-dependent knockdown of candidate genes altered the susceptibility of the human A549 cell line to CS-induced cell death and DAMP release. Furthermore, we tested whether these genes were differentially regulated by CS exposure in bronchial brushings obtained from individuals with a family history indicative of either the presence or absence of susceptibility for COPD. We observed that, of the four DAMPs tested, double-stranded DNA (dsDNA) showed the highest correlation with neutrophilic airway inflammation. Genetic analyses identified 11 candidate genes governing either CS-induced or basal dsDNA release in mice. Two candidate genes ( Elac2 and Ppt1) showed differential expression in lung tissue on CS exposure between susceptible and nonsusceptible mouse strains. Knockdown of ELAC2 and PPT1 in A549 cells altered susceptibility to CS extract-induced cell death and DAMP release. In bronchial brushings, CS-induced expression of ENOX1 and ARGHGEF11 was significantly different between individuals susceptible or nonsusceptible for COPD. Our study shows that genetic variance in a mouse model is associated with CS-induced DAMP release, and that this might contribute to susceptibility for COPD.
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Xu, Fei, Jinpei Lin, Wenqiang Cui, Qing Kong, Qiuping Li, Lulu Li, Ying Wei, and Jingcheng Dong. "Scutellaria baicalensis Attenuates Airway Remodeling via PI3K/Akt/NF-κB Pathway in Cigarette Smoke Mediated-COPD Rats Model." Evidence-Based Complementary and Alternative Medicine 2018 (2018): 1–12. http://dx.doi.org/10.1155/2018/1281420.
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Background. Scutellaria baicalensis (SB) is commonly used in traditional Chinese medicine for chronic inflammatory diseases. This study aims to investigate the effects of the early intervention with SB on airway remodeling in a well-established rat model of COPD induced by cigarette smoking. Methods. COPD model in Sprague Dawley (SD) rats were established by exposing them to smoke for 6 days/week, for 12 weeks, 24 weeks, or 36 weeks. Meanwhile, rats were randomly divided into normal control group, model group, Budesonide (BUD) group, and the SB (low, middle, and high) dose groups with 8 rats in each group and 3 stages (12 weeks, 24 weeks, and 36 weeks). After treatment, the pulmonary function was evaluated by BUXCO system and the morphology changes of the lungs were observed with HE and Masson staining. The serum IL-6, IL-8, and IL-10 and TNF-α, TGF-beta (TGF-β1), MMP-2, MMP-9, and TIMP-1 levels in BALF were detected by ELISA-kit assay. The protein expression levels of AKT and NF-κB (p65) were determined by western blot (WB). Results. The oral of SB significantly improved pulmonary function (PF) and ameliorated the pathological damage and attenuated inflammatory cytokines infiltration into the lungs. Meanwhile, the levels of TGF-β, MMP-2, MMP-9, and TIMP-1 were partially significantly decreased. The levels of PI3K/AKT/NF-κB pathway were also markedly suppressed by SB. Conclusions. SB could significantly improve the condition of airway remodeling by inhibiting airway inflammation and partially quenching TGF-β and MMPs via PI3K/AKT/NF-κB pathway.
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Wright, Joanne L., Manuel Cosio, and Andrew Churg. "Animal models of chronic obstructive pulmonary disease." American Journal of Physiology-Lung Cellular and Molecular Physiology 295, no. 1 (July 2008): L1—L15. http://dx.doi.org/10.1152/ajplung.90200.2008.
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The mechanisms involved in the genesis of chronic obstructive pulmonary disease (COPD) are poorly defined. This area is complicated and difficult to model because COPD consists of four separate anatomic lesions (emphysema, small airway remodeling, pulmonary hypertension, and chronic bronchitis) and a functional lesion, acute exacerbation; moreover, the disease in humans develops over decades. This review discusses the various animal models that have been used to attempt to recreate human COPD and the advantages and disadvantages of each. None of the models reproduces the exact changes seen in humans, but cigarette smoke-induced disease appears to come the closest, and genetically modified animals also, in some instances, shed light on processes that appear to play a role.
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Gao, Congxiao, Reiko Fujinawa, Takayuki Yoshida, Manabu Ueno, Fumi Ota, Yasuhiko Kizuka, Tetsuya Hirayama, et al. "A keratan sulfate disaccharide prevents inflammation and the progression of emphysema in murine models." American Journal of Physiology-Lung Cellular and Molecular Physiology 312, no. 2 (February 1, 2017): L268—L276. http://dx.doi.org/10.1152/ajplung.00151.2016.
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Emphysema is a typical component of chronic obstructive pulmonary disease (COPD), a progressive and inflammatory airway disease. However, no effective treatment currently exists. Here, we show that keratan sulfate (KS), one of the major glycosaminoglycans produced in the small airway, decreased in lungs of cigarette smoke-exposed mice. To confirm the protective effect of KS in the small airway, a disaccharide repeating unit of KS designated L4 ([SO3−-6]Galβ1–4[SO3−-6]GlcNAc) was administered to two murine models: elastase-induced-emphysema and LPS-induced exacerbation of a cigarette smoke-induced emphysema. Histological and microcomputed tomography analyses revealed that, in the mouse elastase-induced emphysema model, administration of L4 attenuated alveolar destruction. Treatment with L4 significantly reduced neutrophil influx, as well as the levels of inflammatory cytokines, tissue-degrading enzymes (matrix metalloproteinases), and myeloperoxidase in bronchoalveolar lavage fluid, suggesting that L4 suppressed inflammation in the lung. L4 consistently blocked the chemotactic migration of neutrophils in vitro. Moreover, in the case of the exacerbation model, L4 inhibited inflammatory cell accumulation to the same extent as that of dexamethasone. Taken together, L4 represents one of the potential glycan-based drugs for the treatment of COPD through its inhibitory action against inflammation.
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da Cunha Moraes, Gabriel, Luana Beatriz Vitoretti, Auriléia Aparecida de Brito, Cintia Estefano Alves, Nicole Cristine Rigonato de Oliveira, Alana dos Santos Dias, Yves Silva Teles Matos, et al. "Low-Level Laser Therapy Reduces Lung Inflammation in an Experimental Model of Chronic Obstructive Pulmonary Disease Involving P2X7 Receptor." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/6798238.
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Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by irreversible airflow limitation, airway inflammation and remodeling, and enlargement of alveolar spaces. COPD is in the top five leading causes of deaths worldwide and presents a high economic cost. However, there are some preventive measures to lower the risk of developing COPD. Low-level laser therapy (LLLT) is a new effective therapy, with very low cost and no side effects. So, our objective was to investigate if LLLT reduces pulmonary alterations in an experimental model of COPD. C57BL/6 mice were submitted to cigarette smoke for 75 days (2x/day). After 60 days to smoke exposure, the treated group was submitted to LLLT (diode laser, 660 nm, 30 mW, and 3 J/cm2) for 15 days and euthanized for morphologic and functional analysis of the lungs. Our results showed that LLLT significantly reduced the number of inflammatory cells and the proinflammatory cytokine secretion such as IL-1β, IL-6, and TNF-α in bronchoalveolar lavage fluid (BALF). We also observed that LLLT decreased collagen deposition as well as the expression of purinergic P2X7 receptor. On the other hand, LLLT increased the IL-10 release. Thus, LLLT can be pointed as a promising therapeutic approach for lung inflammatory diseases as COPD.
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Kim, Mi-Sun, Dong-Seon Kim, Heung Joo Yuk, Seung-Hyung Kim, Won-Kyung Yang, Geum Duck Park, Kyung Seok Kim, Woo Jung Ham, and Yoon-Young Sung. "Siraitia grosvenorii Extract Attenuates Airway Inflammation in a Murine Model of Chronic Obstructive Pulmonary Disease Induced by Cigarette Smoke and Lipopolysaccharide." Nutrients 15, no. 2 (January 16, 2023): 468. http://dx.doi.org/10.3390/nu15020468.
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We studied the activities of Siraitia grosvenorii extracts (SGE) on airway inflammation in a mouse model of chronic obstructive pulmonary disease (COPD) stimulated by cigarette smoke extract (CSE) and lipopolysaccharide (LPS), as well as in LPS-treated human bronchial epithelial cell line (BEAS-2B). SGE improved the viability of LPS-incubated BEAS-2B cells and inhibited the expression and production of inflammatory cytokines. SGE also attenuated the mitogen-activated protein kinase (MAPK)-nuclear factor-kappa B (NF-κB) signaling activated by LPS stimulation in BEAS-2B cells. In mice stimulated by CSE and LPS, we observed the infiltration of immune cells into the airway after COPD induction. SGE reduced the number of activated T cells, B cells, and neutrophils in bronchoalveolar fluid (BALF), lung tissue, mesenteric lymph node, and peripheral blood mononuclear cells, as well as inhibited infiltration into organs and mucus production. The secretion of cytokines in BALF and the expression level of pro-inflammatory cytokines, mucin 5AC, Transient receptor potential vanilloid 1, and Transient receptor potential ankyrin 1 in lung tissue were alleviated by SGE. In addition, to investigate the activity of SGE on expectoration, we evaluated phenol red secretions in the trachea of mice. SGE administration showed the effect of improving expectoration through an increase in phenol red secretion. Consequently, SGE attenuates the airway inflammatory response in CSE/LPS-stimulated COPD. These findings indicate that SGE may be a potential herbal candidate for the therapy of COPD.
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Sarker, Rim S. J., Thomas M. Conlon, Carmela Morrone, Barkha Srivastava, Nur Konyalilar, Stijn E. Verleden, Hasan Bayram, Heinz Fehrenbach, and Ali Önder Yildirim. "CARM1 regulates senescence during airway epithelial cell injury in COPD pathogenesis." American Journal of Physiology-Lung Cellular and Molecular Physiology 317, no. 5 (November 1, 2019): L602—L614. http://dx.doi.org/10.1152/ajplung.00441.2018.
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Chronic obstructive pulmonary disease (COPD) is a life-threatening lung disease. Although cigarette smoke was considered the main cause of development, the heterogeneous nature of the disease leaves it unclear whether other factors contribute to the predisposition or impaired regeneration response observed. Recently, epigenetic modification has emerged to be a key player in the pathogenesis of COPD. The addition of methyl groups to arginine residues in both histone and nonhistone proteins by protein arginine methyltransferases (PRMTs) is an important posttranslational epigenetic modification event regulating cellular proliferation, differentiation, apoptosis, and senescence. Here, we hypothesize that coactivator-associated arginine methyltransferase-1 (CARM1) regulates airway epithelial cell injury in COPD pathogenesis by controlling cellular senescence. Using the naphthalene (NA)-induced mouse model of airway epithelial damage, we demonstrate that loss of CC10-positive club cells is accompanied by a reduction in CARM1-expressing cells of the airway epithelium. Furthermore, Carm1 haploinsuffficent mice showed perturbed club cell regeneration following NA treatment. In addition, CARM1 reduction led to decreased numbers of antisenescent sirtuin 1-expressing cells accompanied by higher p21, p16, and β-galactosidase-positive senescent cells in the mouse airway following NA treatment. Importantly, CARM1-silenced human bronchial epithelial cells showed impaired wound healing and higher β-galactosidase activity. These results demonstrate that CARM1 contributes to airway repair and regeneration by regulating airway epithelial cell senescence.
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Shin, Dong-Uk, Ji-Eun Eom, Hyeon-Ji Song, Sun Young Jung, Thi Van Nguyen, Kyung Min Lim, Ok Hee Chai, et al. "Camellia sinensis L. Alleviates Pulmonary Inflammation Induced by Porcine Pancreas Elastase and Cigarette Smoke Extract." Antioxidants 11, no. 9 (August 28, 2022): 1683. http://dx.doi.org/10.3390/antiox11091683.
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Cigarette smoke (CS) is the major factor in the development of chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide. Furthermore, although Camellia sinensis (CN) has been known as an anti-inflammatory material, the effect of CN has not yet been known on pulmonary inflammation in COPD. Thus, we investigated the protective effects of Camellia sinensis L. extract (CLE) against pulmonary inflammation in porcine pancreas elastase (PPE) and a cigarette smoke extract (CSE)-induced COPD mouse model. Oral administration of CLE suppressed the symptoms such as infiltration of immune cells, cytokines/chemokines secretion, mucus hypersecretion, and injuries of the lung parenchyma. Increased inflammatory responses in COPD are mediated by various immune cells such as airway epithelial cells, neutrophils, and alveolar macrophages. Thus, we investigated the effect and mechanisms of CLE in H292, HL-60, and MH-S cells. The CLE inhibited the expression of IL-6, IL-8, MUC5AC and MUC5B on CSE/LPS-stimulated H292 cells and also suppressed the formation of neutrophil extracellular traps and secretion of neutrophil elastase by inhibiting reactive oxygen species in PMA-induced HL-60 cells. In particular, the CLE suppressed the release of cytokines and chemokines caused by activating the nuclear factor kappa-light-chain-enhancer of activated B via the activation of nuclear factor erythroid-2-related factor 2 and the heme oxygenase-1 pathway in CSE/LPS-stimulated MH-S cells. Therefore, we suggest that the CLE administration be the effective approach for treating or preventing chronic pulmonary diseases such as COPD induced by CS.
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Xiong, Rui, Yue Wu, Qiangen Wu, Levan Muskhelishvili, Kelly Davis, Priya Tripathi, Ying Chen, et al. "Integration of transcriptome analysis with pathophysiological endpoints to evaluate cigarette smoke toxicity in an in vitro human airway tissue model." Archives of Toxicology 95, no. 5 (March 3, 2021): 1739–61. http://dx.doi.org/10.1007/s00204-021-03008-0.
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AbstractExposure to cigarette smoke (CS) is a known risk factor in the pathogenesis of smoking-caused diseases, such as chronic obstructive pulmonary diseases (COPD) and lung cancer. To assess the effects of CS on the function and phenotype of airway epithelial cells, we developed a novel repeated treatment protocol and comprehensively evaluated the progression of key molecular, functional, and structural abnormalities induced by CS in a human in vitro air–liquid-interface (ALI) airway tissue model. Cultures were exposed to CS (diluted with 0.5 L/min, 1.0 L/min, and 4.0 L/min clean air) generated from smoking five 3R4F University of Kentucky reference cigarettes under the International Organization for Standardization (ISO) machine smoking regimen, every other day for 4 weeks (3 days per week, 40 min/day). By integrating the transcriptomics-based approach with the in vitro pathophysiological measurements, we demonstrated CS-mediated effects on oxidative stress, pro-inflammatory cytokines and matrix metalloproteinases (MMPs), ciliary function, expression and secretion of mucins, and squamous cell differentiation that are highly consistent with abnormalities observed in airways of smokers. Enrichment analysis on the transcriptomic profiles of the ALI cultures revealed key molecular pathways, such as xenobiotic metabolism, oxidative stress, and inflammatory responses that were perturbed in response to CS exposure. These responses, in turn, may trigger aberrant tissue remodeling, eventually leading to the onset of respiratory diseases. Furthermore, changes of a panel of genes known to be disturbed in smokers with COPD were successfully reproduced in the ALI cultures exposed to CS. In summary, findings from this study suggest that such an integrative approach may be a useful tool for identifying genes and adverse cellular events caused by inhaled toxicants, like CS.
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Pichl, Alexandra, Natascha Sommer, Mariola Bednorz, Michael Seimetz, Stefan Hadzic, Stefan Kuhnert, Simone Kraut, et al. "Riociguat for treatment of pulmonary hypertension in COPD: a translational study." European Respiratory Journal 53, no. 6 (April 7, 2019): 1802445. http://dx.doi.org/10.1183/13993003.02445-2018.
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Chronic obstructive pulmonary disease (COPD), which comprises the phenotypes of chronic bronchitis and emphysema, is often associated with pulmonary hypertension (PH). However, currently, no approved therapy exists for PH-COPD. Signalling of the nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) axis plays an important role in PH and COPD.We investigated the treatment effect of riociguat, which promotes the NO–cGMP pathway, in the mouse model of smoke-induced PH and emphysema in a curative approach, and retrospectively analysed the effect of riociguat treatment on PH in single patients with PH-COPD.In mice with established PH and emphysema (after 8 months of cigarette smoke exposure), riociguat treatment for another 3 months fully reversed PH. Moreover, histological hallmarks of emphysema were decreased. Microarray analysis revealed involvement of different signalling pathways, e.g. related to matrix metalloproteinases (MMPs). MMP activity was decreased in vivo by riociguat. In PH-COPD patients treated with riociguat (n=7), the pulmonary vascular resistance, airway resistance and circulating MMP levels decreased, while oxygenation at rest was not significantly changed.Riociguat may be beneficial for treatment of PH-COPD. Further long-term prospective studies are necessary to investigate the tolerability, efficacy on functional parameters and effect specifically on pulmonary emphysema in COPD patients.
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Zhang, Huanhuan, Wenying Yu, Liting Ji, Yusen Zhong, Yiyou Lin, Huazhong Ying, Chenhuan Yu, and Changyu Li. "Guifu Dihuang Pills Ameliorated Mucus Hypersecretion by Suppressing Muc5ac Expression and Inactivating the ERK-SP1 Pathway in Lipopolysaccharide/Cigarette Smoke-Induced Mice." Evidence-Based Complementary and Alternative Medicine 2021 (November 3, 2021): 1–15. http://dx.doi.org/10.1155/2021/9539218.
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Mucus hypersecretion is a hallmark of chronic obstructive pulmonary disease (COPD) and is associated with increasing sputum production and declining pulmonary function. Therefore, reducing mucus secretion can be a new therapeutic opportunity for preventing COPD. The Guifu Dihuang pill (GFDHP) is a classical Chinese medicine and has been used as an immunoregulator for treatment of kidney yang deficiency syndrome, including hypothyroidism, adrenocortical hypofunction, chronic bronchitis, and COPD, for more than 2000 years. However, the protective effects and mechanisms of GFDHP against mucus hypersecretion in COPD remain obscure. The aim of the present study was to explore the inhibitory effects of GFDHP on lipopolysaccharide/cigarette smoke- (LPS/CS-) induced Mucin5ac (Muc5ac) overproduction and airway goblet cell hyperplasia in mice. The mice were randomly assigned into 6 groups: control, model, GFDHP-L, GFDHP-M, GFDHP-H, and dexamethasone. The mice were given LPS twice through intranasal inhalation and then exposed to CS daily for 6 weeks. Three doses of GFDHP were orally administered daily during the last 3 weeks of the experiment. Pulmonary function was examined with an EMKA pulmonary system, and pulmonary hyperpermeability and lung damage were evaluated with an in vivo imaging system. Inflammatory cells and cytokines in bronchoalveolar lavage fluid (BALF) were detected with a cell count analyzer and though ELISA analysis, respectively. Lung pathological changes and airway goblet cell hyperplasia were analyzed with hematoxylin and eosin and Alcian blue periodic acid Schiff staining. The protein expression levels of Muc5ac and extracellular signal-regulated kinase (ERK)-specificity protein1 (SP1) signaling pathway were measured with Western blot and immunohistochemistry. The results demonstrated that GFDHP improved pulmonary function and suppressed mouse pulmonary hyperpermeability and edema. GFDHP suppressed inflammatory cell infiltration and cytokine release in BALF, thereby elevating pulmonary function. It ameliorated lung pathological changes and airway goblet cell hyperplasia, and suppressed expression levels of Muc5ac mRNA and protein and phospho-ERK and SP1 levels in the lung tissues of the COPD mice. In conclusion, GFDHP inhibited mucus hypersecretion induced by LPS/CS by suppressing the activation of the ERK-SP1 pathway.
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Xue, H., and MX Li. "MicroRNA-150 protects against cigarette smoke-induced lung inflammation and airway epithelial cell apoptosis through repressing p53: MicroRNA-150 in CS-induced lung inflammation." Human & Experimental Toxicology 37, no. 9 (December 5, 2017): 920–28. http://dx.doi.org/10.1177/0960327117741749.
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Cigarette smoke (CS) exposure is an important risk factor for chronic obstructive pulmonary disease (COPD). MicroRNA-150 (miR-150) is involved in several inflammatory diseases. However, little is known about the role of miR-150 in the pathogenesis of COPD. In this study, we established a CS-related mouse model of COPD and evaluated the impact of miR-150 on CS-induced lung inflammation. We further investigated the effects of miR-150 overexpression on pro-inflammatory cytokine production and apoptosis in airway epithelial cells exposed to CS extract (CSE). It was found that miR-150 was significantly ( p < 0.05) downregulated in the lungs of CS-exposed mice, compared to control mice under normal air. The CSE-exposed BEAS-2B airway epithelial cells displayed a four- to six-fold reduction in miR-150 levels, compared to control cells ( p < 0.05). Delivery of miR-150 mimic attenuated CS-induced lung inflammation and accumulation of neutrophils, lymphocytes, and macrophages in bronchoalveolar lavage fluid. Moreover, miR-150 overexpression prevented the induction of interleukin-6, tumor necrosis factor alpha, and interleukin-8 expression and nuclear factor kappa B (NF-κB) transcriptional activity in BEAS-2B cells by CSE. Additionally, miR-150 protected BEAS-2B cells from CSE-induced apoptosis, which was associated with reduced p53 expression. Co-expression of p53 restored apoptotic response to CSE in miR-150-overexpressing BEAS-2B cells. Collectively, miR-150 suppresses CS-induced lung inflammation and airway epithelial cell apoptosis, which is causally linked to repression of p53 expression and NF-κB activity. Restoration of miR-150 expression may represent a potential therapeutic strategy for CS-related COPD.
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Goswami, Sangeeta, Wade Barranco, Seung-Hyo Lee, Ariel Grudo, David B. Corry, and Farrah Kheradmand. "An autoimmune basis in the disease pathogenesis of COPD/Emphysema (130.41)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S235—S236. http://dx.doi.org/10.4049/jimmunol.178.supp.130.41.
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Abstract Chronic obstructive pulmonary disease (COPD) and emphysema are chronic inflammatory diseases of the lung. Chronic exposure to cigarette smoke is the most common cause of COPD/emphysema however the pathogenesis is not fully understood. Innate immune cells like macrophages and neutrophils are thought to be the most critical factor in the disease pathogenesis. However, we have found that lung and peripheral blood T cells in patients with severe emphysema secrete Th1 cytokines and chemokines when stimulated with elastin peptides in vitro and they have increased anti-elastin antibody as compared to controls. Based on these human studies, we tested the hypothesis that elastin peptides can act as self-antigen and induce an autoimmune lung inflammation in mice. Mice were immunized intra-peritonealy with mouse elastin peptides and adjuvants. Like human COPD, we found increased numbers of activated macrophages and neutrophils as well as increased MMP9 and MMP12 in the airway fluid of elastin immunized mice. Hilar lymph node cells of elastin immunized mice produced more IFN-g upon restimulation with elastin peptides. Additionally, elastin immunized mice had increased anti-elastin antibody titer in the serum and increased IFN-g in the lungs. The establishment of the mouse model of elastin-mediated autoimmune lung inflammation will be critical in elucidating the role of adaptive immune system in pathogenesis of COPD/emphysema.
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Kim, Seung-Hyung, Jung-Hee Hong, Won-Kyung Yang, Jeong-Ho Geum, Hye-Rim Kim, Su-Young Choi, Yun-Mi Kang, Hyo-Jin An, and Young-Cheol Lee. "Herbal Combinational Medication of Glycyrrhiza glabra, Agastache rugosa Containing Glycyrrhizic Acid, Tilianin Inhibits Neutrophilic Lung Inflammation by Affecting CXCL2, Interleukin-17/STAT3 Signal Pathways in a Murine Model of COPD." Nutrients 12, no. 4 (March 27, 2020): 926. http://dx.doi.org/10.3390/nu12040926.
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Chronic obstructive pulmonary disease (COPD) is caused by exposure to toxic particles, such as coal fly ash (CFA), diesel-exhaust particle (DEP), and cigarette smoke (CS), leading to chronic bronchitis, mucus production, and a subsequent lung dysfunction. This study, using a mouse model of COPD, aimed to evaluate the effect of herbal combinational medication of Glycyrrhiza glabra (GG), Agastache rugosa (AR) containing glycyrrhizic acid (GA), and tilianin (TN) as active ingredients. GA, a major active component of GG, possesses a range of pharmacological and biological activities including anti-inflammatory, anti-allergic, anti-oxidative. TN is a major flavonoid that is present in AR. It has been reported to have anti-inflammatory effects of potential utility as an anti-COPD agent. The COPD in the mice model was induced by a challenge with CFA and DEP. BALB/c mice received CFA and DEP alternately three times for 2 weeks to induce COPD. The herbal mixture of GG, AR, and TN significantly decreased the number of neutrophils in the lungs and bronchoalveolar lavage (BAL) fluid. It also significantly reduced the production of C-X-C motif chemokine ligand 2 (CXCL-2), IL-17A, CXCL-1, TNF-α, symmetric dimethylarginine (SDMA) in BALF and CXCL-2, IL-17A, CXCL-1, MUC5AC, transient receptor potential vanilloid-1 (TRPV1), IL-6, COX-2, NOS-II, and TNF-α mRNA expression in the lung tissue. Notably, a combination of GG and AR was more effective at regulating such therapeutic targets than GG or AR alone. The histolopathological lung injury was alleviated by treatment with the herbal mixture and their active ingredients (especially TN). In this study, the herbal combinational mixture more effectively inhibited neutrophilic airway inflammation by regulating the expression of inflammatory cytokines and CXCL-2 by blocking the IL-17/STAT3 pathway. Therefore, a herbal mixture of GG and AR may be a potential therapeutic agent to treat COPD.
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Yang, Yue, Tingting Di, Zixiao Zhang, Jiaxin Liu, Congli Fu, Yan Wu, and Tao Bian. "Dynamic evolution of emphysema and airway remodeling in two mouse models of COPD." BMC Pulmonary Medicine 21, no. 1 (April 26, 2021). http://dx.doi.org/10.1186/s12890-021-01456-z.
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Abstract Background Establishment of a mouse model is important for investigating the mechanism of chronic obstructive pulmonary disease (COPD). In this study, we observed and compared the evolution of the pathology in two mouse models of COPD induced by cigarette smoke (CS) exposure alone or in combination with lipopolysaccharide (LPS). Methods One hundred eight wild-type C57BL/6 mice were equally divided into three groups: the (1) control group, (2) CS-exposed group (CS group), and (3) CS + LPS-exposed group (CS + LPS group). The body weight of the mice was recorded, and noninvasive lung function tests were performed monthly. Inflammation was evaluated by counting the number of inflammatory cells in bronchoalveolar lavage fluid and measuring the expression of the IL-6 mRNA in mouse lung tissue. Changes in pathology were assessed by performing hematoxylin and eosin and Masson staining of lung tissue sections. Results The two treatments induced emphysema and airway remodeling and decreased lung function. Emphysema was induced after 1 month of exposure to CS or CS + LPS, while airway remodeling was induced after 2 months of exposure to CS + LPS and 3 months of exposure to CS. Moreover, the mice in the CS + LPS group exhibited more severe inflammation and airway remodeling than the mice in the CS group, but the two treatments induced similar levels of emphysema. Conclusion Compared with the single CS exposure method, the CS + LPS exposure method is a more suitable model of COPD in airway remodeling research. Conversely, the CS exposure method is a more suitable model of COPD for emphysema research due to its simple operation.
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Wang, Zhigang, Wenzhang Liang, Cuiqing Ma, Jiachao Wang, Xue Gao, and Lin Wei. "Macrophages Inhibit Ciliary Protein Levels by Secreting BMP-2 Leading to Airway Epithelial Remodeling Under Cigarette Smoke Exposure." Frontiers in Molecular Biosciences 8 (April 26, 2021). http://dx.doi.org/10.3389/fmolb.2021.663987.
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Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease with high morbidity and mortality worldwide. So far, smoking is still its leading cause. The characteristics of COPD are emphysema and airway remodeling, as well as chronic inflammation, which were predominated by macrophages. Some studies have reported that macrophages were involved in emphysema and chronic inflammation, but whether there is a link between airway remodeling and macrophages remains unclear. In this study, we found that both acute and chronic cigarette smoke exposure led to an increase of macrophages in the lung and a decrease of ciliated cells in the airway epithelium of a mouse model. The results of in vitro experiments showed that the ciliary protein (β-tubulin-IV) levels of BEAS-2B cells could be inhibited when co-cultured with human macrophage line THP-1, and the inhibitory effect was augmented with the stimulation of cigarette smoke extract (CSE). Based on the results of transcriptome sequencing, we focused on the protein, bone morphogenetic protein-2 (BMP-2), secreted by the macrophage, which might mediate this inhibitory effect. Further studies confirmed that BMP-2 protein inhibited β-tubulin-IV protein levels of BEAS-2B cells under the stimulation of CSE. Coincidentally, this inhibitory effect could be nearly blocked by the BMP receptor inhibitor, LDN, or could be interfered with BMP-2 siRNA. This study suggests that activation and infiltration of macrophages in the lung induced by smoke exposure lead to a high expression of BMP-2, which in turn inhibits the ciliary protein levels of the bronchial epithelial cells, contributing to the remodeling of airway epithelium, and aggravates the development of COPD.
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Tiendrébéogo, Arnaud Jean Florent, Thibaud Soumagne, François Pellegrin, Maylis Dagouassat, Jeanne Tran Van Nhieu, Philippe Caramelle, Emmanuel N. Paul, et al. "The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects." Scientific Reports 13, no. 1 (January 16, 2023). http://dx.doi.org/10.1038/s41598-022-25993-7.
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AbstractSmall airway remodeling (SAR) is a key phenomenon of airflow obstruction in smokers, leading to chronic obstructive pulmonary disease (COPD). SAR results in an increased thickness of small airway walls, with a combination of peribronchiolar fibrosis with increased fibrous tissue and accumulation of mesenchymal and epithelial cells. SAR pathogenesis is still unclear but recent data suggest that alterations in telomerase activity could represent a possible underlying mechanism of SAR. Our study was dedicated to identify a potential protective role of TA-65, a pharmacological telomerase activator, in a cigarette smoke (CS) model of SAR in mice, and to further precise if extra-telomeric effects of telomerase, involving oxidative stress modulation, could explain it. C57BL/6J mice were daily exposed to air or CS during 4 weeks with or without a concomitant administration of TA-65 starting 7 days before CS exposure. Morphological analyses were performed, and mucus production, myofibroblast differentiation, collagen deposition, as well as transforming growth factor-β1 (TGF-β1) expression in the small airway walls were examined. In addition, the effects of TA-65 treatment on TGF-β expression, fibroblast-to-myofibroblast differentiation, reactive oxygen species (ROS) production and catalase expression and activity were evaluated in primary cultures of pulmonary fibroblasts and/or mouse embryonic fibroblasts in vitro. Exposure to CS during 4 weeks induced SAR in mice, characterized by small airway walls thickening and peribronchiolar fibrosis (increased deposition of collagen, expression of α-SMA in small airway walls), without mucus overproduction. Treatment of mice with TA-65 protected them from CS-induced SAR. This effect was associated with the prevention of CS-induced TGF-β expression in vivo, the blockade of TGF-β-induced myofibroblast differentiation, and the reduction of TGF-β-induced ROS production that correlates with an increase of catalase expression and activity. Our findings demonstrate that telomerase is a critical player of SAR, probably through extra-telomeric anti-oxidant effects, and therefore provide new insights in the understanding and treatment of COPD pathogenesis.
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Baek, Eun Bok, Jin-hyung Rho, Eunhye Jung, Chang-Seob Seo, Jin-Hee Kim, and Hyo-Jung Kwun. "Protective effect of Palmijihwanghwan in a mouse model of cigarette smoke and lipopolysaccharide-induced chronic obstructive pulmonary disease." BMC Complementary Medicine and Therapies 21, no. 1 (November 16, 2021). http://dx.doi.org/10.1186/s12906-021-03453-5.
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Abstract Background Palmijihwanghwan (PJH) is a traditional medicine and eight constituents derived from PJH possess anti-inflammatory activities. However, the scientific evidence for its potential as a therapeutic agent for inflammatory lung disease has not yet been studied. In this study, we examined the protective effect of PJH in a mouse model of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke (CS) with lipopolysaccharide (LPS). Methods Mice received CS exposure for 8 weeks and intranasal instillation of LPS on weeks 1, 3, 5 and 7. PJH (100 and 200 mg/kg) was administrated daily 1 h before CS treatment for the last 4 weeks. Results Compared with CS plus LPS-exposed mice, mice in the PJH-treated group showed significantly decreased inflammatory cells count and reduced inflammatory cytokines including interleukin-1 beta (IL-1β), IL-6 and tumor necrosis factor alpha (TNF-α) levels in broncho-alveolar lavage fluid (BALF) and lung tissue. PJH also suppressed the phosphorylation of nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase1/2 (ERK1/2) caused by CS plus LPS exposure. Furthermore, CS plus LPS induced increases in matrix metallopeptidase (MMP)-7, MMP-9, and transforming growth factor-β (TGF-β) expression and collagen deposition that were inhibited in PJH-treated mice. Conclusions This study demonstrates that PJH prevents respiratory inflammation and airway remodeling caused by CS with LPS exposure suggesting potential therapy for the treatment of COPD.
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Van Eeckhoutte, Hannelore P., Chantal Donovan, Richard Y. Kim, Thomas M. Conlon, Meshal Ansari, Haroon Khan, Ranjith Jayaraman, et al. "RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD." European Respiratory Journal, December 22, 2022, 2201506. http://dx.doi.org/10.1183/13993003.01506-2022.
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RationaleReceptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of chronic obstructive pulmonary disease (COPD) pathogenesis.ObjectiveWe aimed to define the contribution of RIPK1 kinase-dependent cell death and inflammation in the pathogenesis of COPD.MethodsWe assessedRIPK1expression in single-cell RNA-sequencing data from human and mouse lungs and validated RIPK1 levels in lung tissue of COPD patientsviaimmunohistochemistry. Next, we assessed the consequences of genetic and pharmacological inhibition of RIPK1 kinase activity in experimental COPD, usingRipk1S25D/S25Dkinase deficient mice and the RIPK1 kinase inhibitor GSK'547.Measurements and main resultsRIPK1expression increased in alveolar type I (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients, compared to never smokers and smokers without airflow limitation. In mice, exposure to cigarette smoke (CS) increasedRipk1expression similarly in AT2 cells, and further in alveolar macrophages and T cells. Genetic and/or pharmacological inhibition of RIPK1 kinase activity significantly attenuated airway inflammation upon acute and subacute CS-exposure, as well as airway remodeling, emphysema and apoptotic and necroptotic cell death upon chronic CS-exposure. Similarly, pharmacological RIPK1 kinase inhibition significantly attenuated elastase-induced emphysema and lung function decline. Finally, RNA-sequencing on lung tissue of CS-exposed mice revealed downregulation of cell death and inflammatory pathways upon pharmacological RIPK1 kinase inhibition.ConclusionsRIPK1 kinase inhibition is protective in experimental models of COPD and may represent a novel promising therapeutic approach.
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Huang, Hua-Qiong, Na Li, Dan-Yang Li, Du Jing, Zheng-Yuan Liu, Xu-Chen Xu, Hai-Pin Chen, et al. "Autophagy Promotes Cigarette Smoke-Initiated and Elastin-Driven Bronchitis-Like Airway Inflammation in Mice." Frontiers in Immunology 12 (March 22, 2021). http://dx.doi.org/10.3389/fimmu.2021.594330.
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Cigarette smoke (CS)-induced macrophage activation and airway epithelial injury are both critical for the development of chronic obstructive pulmonary disease (COPD), while the eventual functions of autophagy in these processes remain controversial. We have recently developed a novel COPD mouse model which is based on the autoimmune response sensitized by CS and facilitated by elastin. In the current study, we therefore utilized this model to investigate the roles of autophagy in different stages of the development of bronchitis-like airway inflammation. Autophagic markers were increased in airway epithelium and lung tissues, and Becn+/- or Lc3b-/- mice exhibited reduced neutrophilic airway inflammation and mucus hyperproduction in this COPD mouse model. Moreover, treatment of an autophagic inhibitor 3-methyladenine (3-MA) either during CS-initiated sensitization or during elastin provocation significantly inhibited the bronchitis-like phenotypes in mice. Short CS exposure rapidly induced expression of matrix metallopeptidase 12 (MMP12) in alveolar macrophages, and treatment of doxycycline, a pan metalloproteinase inhibitor, during CS exposure effectively attenuated the ensuing elastin-induced airway inflammation in mice. CS extract triggered MMP12 expression in cultured macrophages, which was attenuated by autophagy impairment (Becn+/- or Lc3b-/-) or inhibition (3-MA or Spautin-1). These data, taken together, demonstrate that autophagy mediates both the CS-initiated MMP12 activation in macrophages and subsequent airway epithelial injury, eventually contributing to development COPD-like airway inflammation. This study reemphasizes that inhibition of autophagy as a novel therapeutic strategy for CS-induced COPD.
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Kliment, Corrine R., Jennifer M. K. Nguyen, Mary Jane Kaltreider, YaWen Lu, Steven M. Claypool, Josiah E. Radder, Frank C. Sciurba, et al. "Adenine nucleotide translocase regulates airway epithelial metabolism, surface hydration and ciliary function." Journal of Cell Science 134, no. 4 (February 15, 2021). http://dx.doi.org/10.1242/jcs.257162.
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ABSTRACT Airway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive pulmonary disease (COPD), which is impacted by cigarette smoking and has no therapeutic options. We utilized a high-copy cDNA library genetic selection approach in the amoeba Dictyostelium discoideum to identify genetic protectors to cigarette smoke. Members of the mitochondrial ADP/ATP transporter family adenine nucleotide translocase (ANT) are protective against cigarette smoke in Dictyostelium and human bronchial epithelial cells. Gene expression of ANT2 is reduced in lung tissue from COPD patients and in a mouse smoking model, and overexpression of ANT1 and ANT2 resulted in enhanced oxidative respiration and ATP flux. In addition to the presence of ANT proteins in the mitochondria, they reside at the plasma membrane in airway epithelial cells and regulate airway homeostasis. ANT2 overexpression stimulates airway surface hydration by ATP and maintains ciliary beating after exposure to cigarette smoke, both of which are key functions of the airway. Our study highlights a potential for upregulation of ANT proteins and/or of their agonists in the protection from dysfunctional mitochondrial metabolism, airway hydration and ciliary motility in COPD. This article has an associated First Person interview with the first author of the paper.
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Pei, Yuqiang, Jing Zhang, Jingge Qu, Yafei Rao, Danyang Li, Xiaoyan Gai, Yahong Chen, Ying Liang, and Yongchang Sun. "Complement component 3 protects human bronchial epithelial cells from cigarette smoke-induced oxidative stress and prevents incessant apoptosis." Frontiers in Immunology 13 (December 20, 2022). http://dx.doi.org/10.3389/fimmu.2022.1035930.
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The complement component 3 (C3) is a pivotal element of the complement system and plays an important role in innate immunity. A previous study showed that intracellular C3 was upregulated in airway epithelial cells (AECs) from individuals with end-stage chronic obstructive pulmonary disease (COPD). Accumulating evidence has shown that cigarette smoke extract (CSE) induces oxidative stress and apoptosis in AECs. Therefore, we investigated whether C3 modulated cigarette smoke-induced oxidative stress and apoptosis in AECs and participated in the pathogenesis of COPD. We found increased C3 expression, together with increased oxidative stress and apoptosis, in a cigarette smoke-induced mouse model of COPD and in AECs from patients with COPD. Different concentrations of CSEinduced C3 expression in 16HBE cells in vitro. Interestingly, C3 knockdown (KD) exacerbated oxidative stress and apoptosis in 16HBE cells exposed to CSE. Furthermore, C3 exerted its pro-survival effects through JNK inhibition, while exogenous C3 partially rescued CSE-induced cell death and oxidative stress in C3 KD cells. These data indicate that locally produced C3 is an important pro-survival molecule in AECs under cigarette smoke exposure, revealing a potentially novel mechanism in the pathogenesis of COPD.
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Yang, Ye, Lei Huang, Chongchong Tian, and Bingjun Qian. "Magnesium isoglycyrrhizinate inhibits airway inflammation in rats with chronic obstructive pulmonary disease." BMC Pulmonary Medicine 21, no. 1 (November 15, 2021). http://dx.doi.org/10.1186/s12890-021-01745-7.
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Abstract Background Chronic obstructive pulmonary disease (COPD) is a kind of chronic lung diseases with the characteristics of airway remodeling and airflow obstruction. Magnesium isoglycyrrhizinate (MgIG) is an anti-inflammatory glycyrrhizic acid preparation for treating hepatitis. However, whether MgIG can treat other diseases and its action mechanism is still obscure. In this study, we evaluated the anti-inflammatory effect of MgIG in rats with COPD and investigated the underlying mechanisms. Methods Rat model of COPD was constructed by endotracheal-atomized lipopolysaccharide exposure and cigarette smoke induction. Rats were randomly divided into 5 groups: control group, COPD model group, salmeterol fluticasone comparator group, low dose of MgIG group, and high dose of MgIG group. Except for normal control group, the other four groups received sensitization treatment by cigarette smoking and endotracheal-atomization of endotoxin lipopolysaccharide to construct COPD rats model. After model established successfully, the COPD rats in each group received corresponding dose of endotracheal-atomized normal saline, salmeterol fluticasone, and MgIG every day prior to exposure of cigarette smoke from days 30 to 45. Normal control group were treated with normal saline. Finally, All rats were euthanatized. Pulmonary function was measured. Cells in bronchoalveolar lavage fluid were classified, inflammatory factors IL-6 and TNF-α were determined, histopathological analysis was performed by HE staining, and expression of NLRP3 and cleaved caspase-1 in the lung tissue was also determined by Western blotting. Results It showed that MgIG treatment (0.40 or 0.80 mg/kg/day) could recover the weight and the clinical symptoms of rats with COPD, accompanied with lung inflammation infiltration reduction, airway wall attenuation, bronchial mucus secretion reduction. Additionally, MgIG administration reduced inflammatory cells (white blood cells, neutrophils, lymphocytes and monocytes) accumulation in bronchoalveolar lavage fluid and decreased IL-6 and TNF-α production in the serum of COPD rats. Furthermore, MgIG treatment also reduced the expression level of NLRP3 and cleaved caspase-1. Conclusion It indicate that MgIG might be an alternative for COPD treatment, and its mechanism of action might be related to the suppression of NLRP3 inflammasome.
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Zhou, Lei, Bo Wu, Jun Yang, Bing Wang, Jing Pan, Donghui Xu, and Chunling Du. "Knockdown of circFOXO3 ameliorates cigarette smoke-induced lung injury in mice." Respiratory Research 22, no. 1 (November 17, 2021). http://dx.doi.org/10.1186/s12931-021-01883-w.
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Abstract Background Chronic obstructive pulmonary disease (COPD) remains a prevalent chronic airway inflammatory disease. Circular RNAs (circRNAs) are associated with inflammation regulation; therefore, we examined distinct effects of circRNA FOXO3 (circFOXO3) against pneumonic inflammatory processes in COPD. Methods We first quantified and localized circFOXO3 in mouse lung epithelial cell line MLE12 by quantitative reverse-transcription PCR and in situ hybridization. Next, circFOXO3 was suppressed by therapeutic administration of circFOXO3 knockdown lentivirus in mice exposed to air or cigarette smoke (CS) for 12 weeks, and several hallmarks of COPD were evaluated. Results We noticed that circFOXO3 is upregulated in CS-exposed lungs and cigarette smoke extract (CSE)-treated murine alveolar epithelial cells. Knockdown of circFOXO3 attenuated the release of CXCL1 and IL-6 as well as inflammatory processes in the lungs of CS-exposed mice. In addition, we identified miR-214-3p as a circFOXO3-targeted microRNA. MiR-214-3p overexpression exerted protective effects against pneumonic inflammation after CS exposure. Silencing of circFOXO3 downregulated IKK-β mRNA (miR-214-3p’s target), resulting in the dysfunction of the NF-κB signaling pathway and attenuation of CSE-induced inflammatory-cytokine expression. Conclusions Collectively, these findings reveal a crucial function of circFOXO3 in the pathological remodeling related to CS-induced inflammatory processes. Hence, circFOXO3 might be a good target for the treatment of inflammatory disorders similar to CS-induced lung inflammation.
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Rayner, Rachael E., Patrudu Makena, Gaddamanugu L. Prasad, and Estelle Cormet-Boyaka. "Cigarette Smoke Preparations, Not Electronic Nicotine Delivery Systems (ENDS) Preparations, Induce Features of Lung Disease in a 3D Lung Repeat-Dose Model." American Journal of Physiology-Lung Cellular and Molecular Physiology, November 18, 2020. http://dx.doi.org/10.1152/ajplung.00452.2020.
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Cigarette smoking is a risk factor for several lung diseases, including chronic obstructive pulmonary disease, cardiovascular disease and lung cancer. The potential health effects of chronic use of electronic nicotine delivery systems (ENDS) is unclear. This study utilized fully differentiated primary normal human bronchial epithelial (NHBE) cultures in a repeat-dose exposure to evaluate and compare the effect of combustible cigarette and ENDS preparations. We show that 1-hour daily exposure of NHBE cultures over a 10-day period to combustible cigarette whole smoke-conditioned media (WS-CM) increased expression of oxidative stress markers, cell proliferation, airway remodeling, cellular transformation markers, and decreased mucociliary function including ion channel function and airway surface liquid. Conversely, aerosol conditioned media (ACM) from ENDS with similar nicotine concentration (equivalent-nicotine units) as WS-CM and nicotine alone had no effect on those parameters. In conclusion, primary NHBE cultures in a repeat-dose exposure system represent a good model to assess the features of lung disease. This study also reveals that cigarette and ENDS preparations differentially elicit several key endpoints, some of which are potential biomarkers for lung cancer or COPD.
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Xu, Yifan, Jing Li, Zhiwei Lin, Weiquan Liang, Lijie Qin, Jiabin Ding, Shuqi Chen, and Luqian Zhou. "Isorhamnetin Alleviates Airway Inflammation by Regulating the Nrf2/Keap1 Pathway in a Mouse Model of COPD." Frontiers in Pharmacology 13 (March 24, 2022). http://dx.doi.org/10.3389/fphar.2022.860362.
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Chronic obstructive pulmonary disease (COPD) is a severely disabling chronic lung disease characterized by persistent airway inflammation, which leads to limited expiratory airflow that deteriorates over time. Isorhamnetin (Iso) is one of the most important active components in the fruit of Hippophae rhamnoides L. and leaves of Ginkgo biloba L, which is widely used in many pulmonary disease studies because of its anti-inflammatory effects. Here, we investigated the pharmacological action of Iso in CS-induced airway inflammation and dissected the anti-inflammation mechanisms of Iso in COPD mice. A mouse model of COPD was established by exposure to cigarette smoke (CS) and intratracheal inhalation of lipopolysaccharide (LPS). Our results illustrated that Iso treatment significantly reduced leukocyte recruitment and excessive secretion of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and regulated upon activation, normal T-cell expressed and secreted (RANTES) in BALF of CS-induced COPD mice in a dose-dependent manner. This improved airway collagen deposition and emphysema, and further alleviated the decline in lung functions and systemic symptoms of hypoxia and weight loss. Additionally, Iso treatment obviously improves the T lymphocyte dysregualtion in peripheral blood of COPD mice. Mechanistically, Iso may degrade Keap1 through ubiquitination of p62, thereby activating the nuclear factor erythroid 2-related factor (Nrf2) pathway to increase the expression of protective factors, such as heme oxygenase-1 (HO-1), superoxide dismutase (SOD) 1, and SOD2, in lungs of CS-exposed mice, which plays an anti-inflammatory role in COPD. In conclusion, our study indicates that Iso significantly alleviates the inflammatory response in CS-induced COPD mice mainly by affecting the Nrf2/Keap1 pathway. More importantly, Iso exhibited anti-inflammatory effects comparable with Dex in COPD and we did not observe discernible side effects of Iso. The high safety profile of Iso may make it a potential drug candidate for COPD.
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Hao, Dexun, Yanshuang Li, Jiang Shi, and Junguang Jiang. "Baicalin alleviates chronic obstructive pulmonary disease through regulation of HSP72-mediated JNK pathway." Molecular Medicine 27, no. 1 (May 30, 2021). http://dx.doi.org/10.1186/s10020-021-00309-z.
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Abstract Background Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction and progressive lung inflammation. As the primary ingredient of a traditional Chinese medical herb, Baicalin has been previously shown to possess anti-inflammatory abilities. Thus, the current study aimed to elucidate the mechanism by which baicalin alleviates COPD. Methods Baicalin was adopted to treat cigarette smoke in extract-exposed MLE-12 cells after which cell viability and apoptosis were determined. The production of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-8 were determined by enzyme-linked immunoassay. A COPD mouse model was constructed via exposure to cigarette smoke and lipopolysaccharide, baicalin treatment. Lung function and inflammatory cell infiltration were determined and the production of Muc5AC, TNF-α, IL-6, IL-8 in the bronchoalveolar lavage fluid (BALF) was assayed by ELISA. The effect of HSP72 and JNK on COPD following treatment with baicalin was assessed both in vivo and in vitro by conducting loss- and gain- function experiments. Results Baicalin improved lung function evidenced by reduction in inflammatory cell infiltration and Muc5AC, TNF-α, IL-6 and IL-8 levels observed in BALF in mice. Baicalin was further observed to elevate cell viability while inhibited apoptosis and TNF-α, IL-6 and IL-8 levels in MLE-12 cells. Baicalin treatment increased HSP72 expression, while its depletion reversed the effect of baicalin on COPD. HSP72 inhibited the activation of JNK, while JNK activation was found to inhibit the effect of baicalin on COPD. Conclusions Baicalin upregulated the expression of HSP72, resulting in the inhibition of JNK signaling activation, which ultimately alleviates COPD.
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Li, Hongtao, Qimei Ye, Yusen Lin, Xuena Yang, Xiaoling Zou, Hailing Yang, Wenbin Wu, Ping Meng, and Tiantuo Zhang. "CpG oligodeoxynucleotides attenuate RORγt-mediated Th17 response by restoring histone deacetylase-2 in cigarette smoke-exposure asthma." Cell & Bioscience 11, no. 1 (May 20, 2021). http://dx.doi.org/10.1186/s13578-021-00607-3.
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Abstract Background Cigarette smoke (CS) exposure increases corticosteroid insensitive asthma related to increased Th17 phenotype, and new treatment strategies are needed for CS-associated asthma. Histone deacetylase 2 (HDAC2), found in the airway epithelium, is critical for ameliorating glucocorticoids insensitivity. We recently demonstrated the anti-inflammatory effects of CpG oligodeoxynucleotides (CpG-ODNs) on CS-exposure asthma. However, the effects of CpG-ODNs on HDAC2 expression and enzymatic activity remain unclear. This study aimed to assess whether CpG-ODNs protect against excessive Th17 immune responses in CS-induced asthma through HDAC2-dependent mechanisms and compared their effects with those of corticosteroids. Methods The effects of CpG-ODNs alone and in combination with budesonide (BUD) on airway inflammation and Th2/Th17-related airway immune responses were determined using an in vivo model of CS-induced asthma and in cultured bronchial epithelial (HBE) cells administered ovalbumin (OVA) and/or cigarette smoke extract (CSE). HDAC2 and retinoid-related orphan nuclear receptor γt (RORγt) expression were also assessed in mouse lung specimens and HBE cells. Results CpG-ODNs and BUD synergistically attenuated CS exposure asthmatic responses in vivo by modulating the influx of eosinophils and neutrophils, airway remodeling, Th2/Th17 associated cytokine and chemokine production, and airway hyperresponsiveness and blocking RORγt-mediated Th17 inflammation through induced HDAC2 expression/activity. In vitro, CpG-ODNs synergized with BUD to inhibit Th17 cytokine production in OVA- and CSE-challenged HBE cells while suppressing RORγt and increasing epithelial HDAC2 expression/activity. Conclusions CpG-ODNs reversed CS-induced HDAC2 downregulation and enhanced the sensitivity of CS-exposed asthmatic mice and CSE-induced HBE cells to glucocorticoid treatment. This effect may be associated with HDAC2 restoration via RORγt/IL-17 pathway regulation, suggesting that CpG-ODNs are potential corticosteroid-sparing agents for use in CS-induced asthma with Th17-biased immune conditions.
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Noël, Alexandra, Zakia Perveen, Rui Xiao, Harriet Hammond, Viviana Le Donne, Kelsey Legendre, Manas Ranjan Gartia, Sushant Sahu, Daniel B. Paulsen, and Arthur L. Penn. "Mmp12 Is Upregulated by in utero Second-Hand Smoke Exposures and Is a Key Factor Contributing to Aggravated Lung Responses in Adult Emphysema, Asthma, and Lung Cancer Mouse Models." Frontiers in Physiology 12 (November 29, 2021). http://dx.doi.org/10.3389/fphys.2021.704401.
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Matrix metalloproteinase-12 (Mmp12) is upregulated by cigarette smoke (CS) and plays a critical role in extracellular matrix remodeling, a key mechanism involved in physiological repair processes, and in the pathogenesis of emphysema, asthma, and lung cancer. While cigarette smoking is associated with the development of chronic obstructive pulmonary diseases (COPD) and lung cancer, in utero exposures to CS and second-hand smoke (SHS) are associated with asthma development in the offspring. SHS is an indoor air pollutant that causes known adverse health effects; however, the mechanisms by which in utero SHS exposures predispose to adult lung diseases, including COPD, asthma, and lung cancer, are poorly understood. In this study, we tested the hypothesis that in utero SHS exposure aggravates adult-induced emphysema, asthma, and lung cancer.Methods: Pregnant BALB/c mice were exposed from gestational days 6–19 to either 3 or 10mg/m3 of SHS or filtered air. At 10, 11, 16, or 17weeks of age, female offspring were treated with either saline for controls, elastase to induce emphysema, house-dust mite (HDM) to initiate asthma, or urethane to promote lung cancer. At sacrifice, specific disease-related lung responses including lung function, inflammation, gene, and protein expression were assessed.Results: In the elastase-induced emphysema model, in utero SHS-exposed mice had significantly enlarged airspaces and up-regulated expression of Mmp12 (10.3-fold compared to air-elastase controls). In the HDM-induced asthma model, in utero exposures to SHS produced eosinophilic lung inflammation and potentiated Mmp12 gene expression (5.7-fold compared to air-HDM controls). In the lung cancer model, in utero exposures to SHS significantly increased the number of intrapulmonary metastases at 58weeks of age and up-regulated Mmp12 (9.3-fold compared to air-urethane controls). In all lung disease models, Mmp12 upregulation was supported at the protein level.Conclusion: Our findings revealed that in utero SHS exposures exacerbate lung responses to adult-induced emphysema, asthma, and lung cancer. Our data show that MMP12 is up-regulated at the gene and protein levels in three distinct adult lung disease models following in utero SHS exposures, suggesting that MMP12 is central to in utero SHS-aggravated lung responses.