Academic literature on the topic 'Airway remodeling, Mouse model, COPD, Cigarette smoke'

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.

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.

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.

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.

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.

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.

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.

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.

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.

Chronic Obstructive Pulmonary Disease (COPD) is a progressive and debilitating disease, associated primarily with cigarette smoke exposure, and it is characterized by chronic inflammation of the airways and lung parenchyma and changes in the pulmonary vasculature. Four anatomic lesions are recognizable in COPD: emphysema, small airway remodeling (SAR), vascular remodeling, which may be associated with pulmonary hypertension, and chronic bronchitis, characterized by excessive mucus secretion. Several mechanisms are presumed to cause these changes and support related symptoms. In particular, chronic inflammation and its related consequences, which include epithelial necrosis and apoptosis, changes in cell phenotype and function, proliferation and compartmentalization of specific cells in some pulmonary areas, and deposition of excessive extracellular matrix, have been implicated as the cause of the different clinical presentations of COPD. Although a lot of studies have been carried out in the last twenty years, many facets of the pathogenesis of COPD are not fully understood. Some murine strains mirror some human phenotypes after smoke exposure. Therefore, it was of interest to investigate in these strains whether changes in different endogenous factors, whose expression can influence alveolar destruction, repair and anatomical remodeling, are associated with changes characterizing different phenotypes of the disease. This study has been approached by using immunohistochemistry in order to have information on the expression and distribution of these factors in pulmonary structures at selected time points after the start of smoke exposure. By using this methodological approach, the expression of important fibrogenic cytokines (i.e. TGF-β, PDGF-B and CTGF) at various time points after cigarette smoke exposure have been investigated in C57 Bl/6J mice, which develop significant emphysema, and DBA/2 mice that develop changes similar to those of the "pulmonary fibrosis /emphysema syndrome”. Some other factors that are indicative of apoptosis (cleaved caspase-3), senescence (p16ink4A and p21), regeneration (PCNA and Ki-67) or are implicated in fibrosis resolution and in apoptosis resistance (MyoD) were studied. In order to evaluate the involvement of these factors in parenchymal (i.e., vascular and peri-bronchiolar fibrosis) and airways remodeling (such as goblet cell metaplasia, fibrous and muscular remodeling), we used specific staining techniques (i.e., Masson’s trichrome and PAS staining) or an immunohistochemical analysis for -SMA, at the various experimental time points. A further investigation has been carried out to investigate the expression of three purinergic receptors (i.e. P2X4, P2X7 and P2Y2), which have been recently involved in COPD pathogenesis by acting as danger signals and important mediators of inflammation. The data obtained suggest that apoptosis, senescence and proliferation, that are induced at different rate and time points by inflammatory and fibrotic cytokines, play a role in early or late appearance of the remodeling processes that we observe in these strains of mice. Additionally, the necrosis of alveolar epithelial cells caused by enzyme release and oxidative damage (as revealed by MMP-9 and 8-OHdG positivity) characterize, at different extent, the lung responses of C57 Bl/6J and DBA/2 mice. The activation of purinergic receptors may be due to the release of alarmins, such as ATP and UTP, (which are the main ligands for P2X4, P2X7 and P2Y2) following the necrosis of alveolar epithelial cells.