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Journal articles on the topic 'Lung wound repair'
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1
Kim, Sean H. J., Michael A. Matthay, Keith Mostov, and C. Anthony Hunt. "Simulation of lung alveolar epithelial wound healing in vitro." Journal of The Royal Society Interface 7, no. 49 (March 17, 2010): 1157–70. http://dx.doi.org/10.1098/rsif.2010.0041.
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The mechanisms that enable and regulate alveolar type II (AT II) epithelial cell wound healing in vitro and in vivo remain largely unknown and need further elucidation. We used an in silico AT II cell-mimetic analogue to explore and better understand plausible wound healing mechanisms for two conditions: cyst repair in three-dimensional cultures and monolayer wound healing. Starting with the analogue that validated for key features of AT II cystogenesis in vitro , we devised an additional cell rearrangement action enabling cyst repair. Monolayer repair was enabled by providing ‘cells’ a control mechanism to switch automatically to a repair mode in the presence of a distress signal. In cyst wound simulations, the revised analogue closed wounds by adhering to essentially the same axioms available for alveolar-like cystogenesis. In silico cell proliferation was not needed. The analogue recovered within a few simulation cycles but required a longer recovery time for larger or multiple wounds. In simulated monolayer wound repair, diffusive factor-mediated ‘cell’ migration led to repair patterns comparable to those of in vitro cultures exposed to different growth factors. Simulations predicted directional cell locomotion to be critical for successful in vitro wound repair. We anticipate that with further use and refinement, the methods used will develop as a rigorous, extensible means of unravelling mechanisms of lung alveolar repair and regeneration.
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Gazdhar, Amiq, Patrick Fachinger, Coretta van Leer, Jaroslaw Pierog, Mathias Gugger, Robert Friis, Ralph A. Schmid, and Thomas Geiser. "Gene transfer of hepatocyte growth factor by electroporation reduces bleomycin-induced lung fibrosis." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 2 (February 2007): L529—L536. http://dx.doi.org/10.1152/ajplung.00082.2006.
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Abnormal alveolar wound repair contributes to the development of pulmonary fibrosis after lung injury. Hepatocyte growth factor (HGF) is a potent mitogenic factor for alveolar epithelial cells and may therefore improve alveolar epithelial repair in vitro and in vivo. We hypothesized that HGF could increase alveolar epithelial repair in vitro and improve pulmonary fibrosis in vivo. Alveolar wound repair in vitro was determined using an epithelial wound repair model with HGF-transfected A549 alveolar epithelial cells. Electroporation-mediated, nonviral gene transfer of HGF in vivo was performed 7 days after bleomycin-induced lung injury in the rat. Alveolar epithelial repair in vitro was increased after transfection of wounded epithelial monolayers with a plasmid encoding human HGF, pCikhHGF [human HGF (hHGF) gene expressed from the cytomegalovirus (CMV) immediate-early promoter and enhancer] compared with medium control. Electroporation-mediated in vivo HGF gene transfer using pCikhHGF 7 days after intratracheal bleomycin reduced pulmonary fibrosis as assessed by histology and hydroxyproline determination 14 days after bleomycin compared with controls treated with the same vector not containing the HGF sequence (pCik). Lung epithelial cell proliferation was increased and apoptosis reduced in hHGF-treated lungs compared with controls, suggesting increased alveolar epithelial repair in vivo. In addition, profibrotic transforming growth factor-β1 (TGF-β1) was decreased in hHGF-treated lungs, indicating an involvement of TGF-β1 in hHGF-induced reduction of lung fibrosis. In conclusion, electroporation-mediated gene transfer of hHGF decreases bleomycin-induced pulmonary fibrosis, possibly by increasing alveolar epithelial cell proliferation and reducing apoptosis, resulting in improved alveolar wound repair.
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Crane, Meredith, Yun Xu, William L. Henry, Jorge E. Albina, and Amanda M. Jamieson. "The impact of lung infection on wound repair responses." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 61.10. http://dx.doi.org/10.4049/jimmunol.196.supp.61.10.
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Abstract The incidence of pulmonary infection is elevated in patients with traumatic injury, and the severity of disease, morbidity, and mortality is positively correlated with the degree of trauma. While this clinical problem is well documented, its mechanistic basis is not well understood. Current models are designed to assess the effect of trauma on the development of pneumonia, but lack the ability to measure the subsequent effect of lung infection on wound repair. We have established a model that allows for the simultaneous assessment of wound healing and lung responses in mice with surgical wounds and Influenza A virus (IAV) infection. Mice are wounded by the subcutaneous implantation of sterile polyvinyl alcohol (PVA) sponges or by excision of tail skin and infected with IAV 24 hours later. PVA sponge implantation allows for the assessment of cellular and cytokine responses to injury, while excisional tail wounding allows for the measurement of rate of repair. Our data demonstrate that IAV infection results in delayed wound repair. Furthermore, the wounds of infected mice have lower repair cytokine concentrations and decreased cellularity, mediated in part by impaired trafficking of Ly6Chi monocytes. Wounded mice with IAV infection also have elevated concentrations of proinflammatory cytokines and chemokines in the serum and bronchoalveolar lavage fluid, suggesting an inflated systemic inflammatory response. Taken together, these data indicate that the presence of viral lung infection impairs the normal progression of wound repair. Future studies will determine whether this effect is specific to viral infection, or whether other lung injuries including pulmonary bacterial infection have a similar effect on wound repair responses.
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Olsen, Colin E., Andrew E. Liguori, Yue Zong, R. Clark Lantz, Jefferey L. Burgess, and Scott Boitano. "Arsenic upregulates MMP-9 and inhibits wound repair in human airway epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 295, no. 2 (August 2008): L293—L302. http://dx.doi.org/10.1152/ajplung.00134.2007.
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As part of the innate immune defense, the polarized conducting lung epithelium acts as a barrier to keep particulates carried in respiration from underlying tissue. Arsenic is a metalloid toxicant that can affect the lung via inhalation or ingestion. We have recently shown that chronic exposure of mice or humans to arsenic (10–50 ppb) in drinking water alters bronchiolar lavage or sputum proteins consistent with reduced epithelial cell migration and wound repair in the airway. In this report, we used an in vitro model to examine effects of acute exposure of arsenic (15–290 ppb) on conducting airway lung epithelium. We found that arsenic at concentrations as low as 30 ppb inhibits reformation of the epithelial monolayer following scrape wounds of monolayer cultures. In an effort to understand functional contributions to epithelial wound repair altered by arsenic, we showed that acute arsenic exposure increases activity and expression of matrix metalloproteinase (MMP)-9, an important protease in lung function. Furthermore, inhibition of MMP-9 in arsenic-treated cells improved wound repair. We propose that arsenic in the airway can alter the airway epithelial barrier by restricting proper wound repair in part through the upregulation of MMP-9 by lung epithelial cells.
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Geiser, Thomas, Masanobu Ishigaki, Coretta van Leer, Michael A. Matthay, and V. Courtney Broaddus. "H2O2 inhibits alveolar epithelial wound repair in vitro by induction of apoptosis." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 2 (August 2004): L448—L453. http://dx.doi.org/10.1152/ajplung.00177.2003.
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Reactive oxygen species (ROS) are released into the alveolar space and contribute to alveolar epithelial damage in patients with acute lung injury. However, the role of ROS in alveolar repair is not known. We studied the effect of ROS in our in vitro wound healing model using either human A549 alveolar epithelial cells or primary distal lung epithelial cells. We found that H2O2 inhibited alveolar epithelial repair in a concentration-dependent manner. At similar concentrations, H2O2 also induced apoptosis, an effect seen particularly at the edge of the wound, leading us to hypothesize that apoptosis contributes to H2O2-induced inhibition of wound repair. To learn the role of apoptosis, we blocked caspases with the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (zVAD). In the presence of H2O2, zVAD inhibited apoptosis, particularly at the wound edge and, most importantly, maintained alveolar epithelial wound repair. In H2O2-exposed cells, zVAD also maintained cell viability as judged by improved cell spreading and/or migration at the wound edge and by a more normal mitochondrial potential difference compared with cells not treated with zVAD. In conclusion, H2O2 inhibits alveolar epithelial wound repair in large part by induction of apoptosis. Inhibition of apoptosis can maintain wound repair and cell viability in the face of ROS. Inhibiting apoptosis may be a promising new approach to improve repair of the alveolar epithelium in patients with acute lung injury.
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Croasdell Lucchini, Amanda, Naomi N. Gachanja, Adriano G. Rossi, David A. Dorward, and Christopher D. Lucas. "Epithelial Cells and Inflammation in Pulmonary Wound Repair." Cells 10, no. 2 (February 5, 2021): 339. http://dx.doi.org/10.3390/cells10020339.
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Respiratory diseases are frequently characterised by epithelial injury, airway inflammation, defective tissue repair, and airway remodelling. This may occur in a subacute or chronic context, such as asthma and chronic obstructive pulmonary disease, or occur acutely as in pathogen challenge and acute respiratory distress syndrome (ARDS). Despite the frequent challenge of lung homeostasis, not all pulmonary insults lead to disease. Traditionally thought of as a quiescent organ, emerging evidence highlights that the lung has significant capacity to respond to injury by repairing and replacing damaged cells. This occurs with the appropriate and timely resolution of inflammation and concurrent initiation of tissue repair programmes. Airway epithelial cells are key effectors in lung homeostasis and host defence; continual exposure to pathogens, toxins, and particulate matter challenge homeostasis, requiring robust defence and repair mechanisms. As such, the epithelium is critically involved in the return to homeostasis, orchestrating the resolution of inflammation and initiating tissue repair. This review examines the pivotal role of pulmonary airway epithelial cells in initiating and moderating tissue repair and restitution. We discuss emerging evidence of the interactions between airway epithelial cells and candidate stem or progenitor cells to initiate tissue repair as well as with cells of the innate and adaptive immune systems in driving successful tissue regeneration. Understanding the mechanisms of intercellular communication is rapidly increasing, and a major focus of this review includes the various mediators involved, including growth factors, extracellular vesicles, soluble lipid mediators, cytokines, and chemokines. Understanding these areas will ultimately identify potential cells, mediators, and interactions for therapeutic targeting.
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Clark, Richard A. "The Commonality of Cutaneous Wound Repair and Lung Injury." Chest 99, no. 3 (March 1991): 57S—60S. http://dx.doi.org/10.1378/chest.99.3_supplement.57s.
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Ito, Yoko, Kelly Correll, John A. Schiel, Jay H. Finigan, Rytis Prekeris, and Robert J. Mason. "Lung fibroblasts accelerate wound closure in human alveolar epithelial cells through hepatocyte growth factor/c-Met signaling." American Journal of Physiology-Lung Cellular and Molecular Physiology 307, no. 1 (July 1, 2014): L94—L105. http://dx.doi.org/10.1152/ajplung.00233.2013.
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There are 190,600 cases of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) each year in the United States, and the incidence and mortality of ALI/ARDS increase dramatically with age. Patients with ALI/ARDS have alveolar epithelial injury, which may be worsened by high-pressure mechanical ventilation. Alveolar type II (ATII) cells are the progenitor cells for the alveolar epithelium and are required to reestablish the alveolar epithelium during the recovery process from ALI/ARDS. Lung fibroblasts (FBs) migrate and proliferate early after lung injury and likely are an important source of growth factors for epithelial repair. However, how lung FBs affect epithelial wound healing in the human adult lung has not been investigated in detail. Hepatocyte growth factor (HGF) is known to be released mainly from FBs and to stimulate both migration and proliferation of primary rat ATII cells. HGF is also increased in lung tissue, bronchoalveolar lavage fluid, and serum in patients with ALI/ARDS. Therefore, we hypothesized that HGF secreted by FBs would enhance wound closure in alveolar epithelial cells (AECs). Wound closure was measured using a scratch wound-healing assay in primary human AEC monolayers and in a coculture system with FBs. We found that wound closure was accelerated by FBs mainly through HGF/c-Met signaling. HGF also restored impaired wound healing in AECs from the elderly subjects and after exposure to cyclic stretch. We conclude that HGF is the critical factor released from FBs to close wounds in human AEC monolayers and suggest that HGF is a potential strategy for hastening alveolar repair in patients with ALI/ARDS.
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Geiser, Thomas, Pierre-Henri Jarreau, Kamran Atabai, and Michael A. Matthay. "Interleukin-1β augments in vitro alveolar epithelial repair." American Journal of Physiology-Lung Cellular and Molecular Physiology 279, no. 6 (December 1, 2000): L1184—L1190. http://dx.doi.org/10.1152/ajplung.2000.279.6.l1184.
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Biologically active interleukin (IL)-1β is present in the pulmonary edema fluid obtained from patients with acute lung injury and has been implicated as an important early mediator of nonpulmonary epithelial wound repair. Therefore, we tested the hypothesis that IL-1β would enhance wound repair in cultured monolayers from rat alveolar epithelial type II cells. IL-1β (20 ng/ml) increased the rate of in vitro alveolar epithelial repair by 118 ± 11% compared with that in serum-free medium control cells ( P < 0.01). IL-1β induced cell spreading and migration at the edge of the wound but not proliferation. Neutralizing antibodies to epidermal growth factor (EGF) and transforming growth factor-α or inhibition of the EGF receptor by tyrphostin AG-1478 or genistein inhibited IL-1β-induced alveolar epithelial repair, indicating that IL-1β enhances in vitro alveolar epithelial repair by an EGF- or transforming growth factor-α-dependent mechanism. Moreover, the mitogen-activated protein kinase pathway is involved in IL-1β-induced alveolar epithelial repair because inhibition of extracellular signal-regulated kinase activation by PD-98059 inhibited IL-1β-induced alveolar epithelial repair. In conclusion, IL-1β augments in vitro alveolar epithelial repair, indicating a possible novel role for IL-1β in the early repair process of the alveolar epithelium in acute lung injury.
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Conese, Massimo, and Sante Di Gioia. "Pathophysiology of Lung Disease and Wound Repair in Cystic Fibrosis." Pathophysiology 28, no. 1 (March 10, 2021): 155–88. http://dx.doi.org/10.3390/pathophysiology28010011.
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Cystic fibrosis (CF) is an autosomal recessive, life-threatening condition affecting many organs and tissues, the lung disease being the chief cause of morbidity and mortality. Mutations affecting the CF Transmembrane Conductance Regulator (CFTR) gene determine the expression of a dysfunctional protein that, in turn, triggers a pathophysiological cascade, leading to airway epithelium injury and remodeling. In vitro and in vivo studies point to a dysregulated regeneration and wound repair in CF airways, to be traced back to epithelial CFTR lack/dysfunction. Subsequent altered ion/fluid fluxes and/or signaling result in reduced cell migration and proliferation. Furthermore, the epithelial-mesenchymal transition appears to be partially triggered in CF, contributing to wound closure alteration. Finally, we pose our attention to diverse approaches to tackle this defect, discussing the therapeutic role of protease inhibitors, CFTR modulators and mesenchymal stem cells. Although the pathophysiology of wound repair in CF has been disclosed in some mechanisms, further studies are warranted to understand the cellular and molecular events in more details and to better address therapeutic interventions.
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Xin, Xi, Liu Yan, Zhu Guangfa, Huang Yan, Li Keng, and Wu Chunting. "Mesenchymal Stem Cells Promoted Lung Wound Repair through Hox A9 during Endotoxemia-Induced Acute Lung Injury." Stem Cells International 2017 (2017): 1–8. http://dx.doi.org/10.1155/2017/3648020.
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Objectives. Acute lung injury (ALI) is a common clinical critical disease. Stem cells transplantation is recognized as an effective way to repair injured lung tissues. The present study was designed to evaluate the effects of mesenchymal stem cells (MSCs) on repair of lung and its mechanism. Methods. MSCs carrying GFP were administrated via trachea into wild-type SD rats 4 hours later after LPS administration. The lung histological pathology and the distribution of MSCs were determined by HE staining and fluorescence microscopy, respectively. Next, differentially expressed HOX genes were screened by using real-time PCR array and abnormal expression and function of Hox A9 were analyzed in the lung and the cells. Results. MSCs promoted survival rate of ALI animals. The expression levels of multiple HOX genes had obvious changes after MSCs administration and HOX A9 gene increased by 5.94-fold after MSCs administration into ALI animals. HOX A9 was distributed in endothelial cells and epithelial cells in animal models and overexpression of Hox A9 can promote proliferation and inhibit inflammatory adhesion of MSCs. Conclusion. HoxA9 overexpression induced by MSCs may be closely linked with lung repair after endotoxin shock.
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Geiser, Thomas K., Barbara I. Kazmierczak, Lynne K. Garrity-Ryan, Michael A. Matthay, and Joanne N. Engel. "Pseudomonas aeruginosa ExoT inhibits in vitro lung epithelial wound repair." Cellular Microbiology 3, no. 4 (April 2001): 223–36. http://dx.doi.org/10.1046/j.1462-5822.2001.00107.x.
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Zheng, Shengxing, Vijay K. D'Souza, Domokos Bartis, Rachel C. A. Dancer, Dhruv Parekh, Babu Naidu, Fang Gao-Smith, et al. "Lipoxin A4promotes lung epithelial repair whilst inhibiting fibroblast proliferation." ERJ Open Research 2, no. 3 (July 2016): 00079–2015. http://dx.doi.org/10.1183/23120541.00079-2015.
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Therapy that promotes epithelial repair whilst protecting against fibroproliferation is critical for restoring lung function in acute and chronic respiratory diseases.Primary human alveolar type II cells were used to model the effects of lipoxin A4in vitroupon wound repair, proliferation, apoptosis and transdifferention. Effects of lipoxin A4upon primary human lung fibroblast proliferation, collagen production, and myofibroblast differentiation were also assessed.Lipoxin A4promoted type II cell wound repair and proliferation, blocked the negative effects of soluble Fas ligand/tumour necrosis factor α upon cell proliferation, viability and apoptosis, and augmented the epithelial cell proliferative response to bronchoaveolar lavage fluid (BALF) from acute respiratory distress syndrome (ARDS). In contrast, Lipoxin A4reduced fibroblast proliferation, collagen production and myofibroblast differentiation induced by transforming growth factor β and BALF from ARDS. The effects of Lipoxin A4were phosphatidylinositol 3′-kinase dependent and mediatedviathe lipoxin A4receptor.Lipoxin A4appears to promote alveolar epithelial repair by stimulating epitheial cell wound repair, proliferation, reducing apoptosis and promoting trans-differentiation of alveolar type II cells into type I cells. Lipoxin A4reduces fibroblast proliferation, collagen production and myofibroblast differentiation. These data suggest that targeting lipoxin actions may be a therapeutic strategy for treating the resolution phase of ARDS.
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Blokland, Kaj E. C., David W. Waters, Michael Schuliga, Jane Read, Simon D. Pouwels, Christopher L. Grainge, Jade Jaffar, et al. "Senescence of IPF Lung Fibroblasts Disrupt Alveolar Epithelial Cell Proliferation and Promote Migration in Wound Healing." Pharmaceutics 12, no. 4 (April 24, 2020): 389. http://dx.doi.org/10.3390/pharmaceutics12040389.
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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by excessive accumulation of lung fibroblasts (LFs) and collagen in the lung parenchyma. The mechanisms that underlie IPF pathophysiology are thought to reflect repeated alveolar epithelial injury leading to an aberrant wound repair response. Recent work has shown that IPF-LFs display increased characteristics of senescence including growth arrest and a senescence-associated secretory phenotype (SASP) suggesting that senescent LFs contribute to dysfunctional wound repair process. Here, we investigated the influence of senescent LFs on alveolar epithelial cell repair responses in a co-culture system. Alveolar epithelial cell proliferation was attenuated when in co-culture with cells or conditioned media from, senescence-induced control LFs or IPF-LFs. Cell-cycle analyses showed that a larger number of epithelial cells were arrested in G2/M phase when co-cultured with IPF-LFs, than in monoculture. Paradoxically, the presence of LFs resulted in increased A549 migration after mechanical injury. Our data suggest that senescent LFs may contribute to aberrant re-epithelialization by inhibiting proliferation in IPF.
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Ulldemolins, Anna, Alicia Jurado, Carolina Herranz-Diez, Núria Gavara, Jorge Otero, Ramon Farré, and Isaac Almendros. "Lung Extracellular Matrix Hydrogels-Derived Vesicles Contribute to Epithelial Lung Repair." Polymers 14, no. 22 (November 14, 2022): 4907. http://dx.doi.org/10.3390/polym14224907.
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The use of physiomimetic decellularized extracellular matrix-derived hydrogels is attracting interest since they can modulate the therapeutic capacity of numerous cell types, including mesenchymal stromal cells (MSCs). Remarkably, extracellular vesicles (EVs) derived from MSCs display similar functions as their parental cells, mitigating tissue damage in lung diseases. However, recent data have shown that ECM-derived hydrogels could release other resident vesicles similar to EVs. Here, we aim to better understand the contribution of EVs and ECM-vesicles released from MSCs and/or lung-derived hydrogel (L-HG) in lung repair by using an in vitro lung injury model. L-HG derived-vesicles and MSCs EVs cultured either in L-HG or conventional plates were isolated and characterized. The therapeutic capacity of vesicles obtained from each experimental condition was tested by using an alveolar epithelial wound-healing assay. The number of ECM-vesicles released from acellular L-HG was 10-fold greater than EVs from conventional MSCs cell culture revealing that L-HG is an important source of bioactive vesicles. MSCs-derived EVs and L-HG vesicles have similar therapeutic capacity in lung repair. However, when wound closure rate was normalized by total proteins, the MSCs-derived EVs shows higher therapeutic potential to those released by L-HG. The EVs released from L-HG must be considered when HG is used as substrate for cell culture and EVs isolation.
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Desai, Leena P., Ashish M. Aryal, Bogdan Ceacareanu, Aviv Hassid, and Christopher M. Waters. "RhoA and Rac1 are both required for efficient wound closure of airway epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 6 (December 2004): L1134—L1144. http://dx.doi.org/10.1152/ajplung.00022.2004.
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Repair of the airway epithelium after injury is critical for restoring normal lung. The reepithelialization process involves spreading and migration followed later by cell proliferation. Rho-GTPases are key components of the wound healing process in many different types of tissues, but the specific roles for RhoA and Rac1 vary and have not been identified in lung epithelial cells. We investigated whether RhoA and Rac1 regulate wound closure of bronchial epithelial cells. RhoA and Rac1 proteins were efficiently expressed in a cell line of human bronchial epithelial cells (16HBE) by adenovirus-based gene transfer. We found that both constitutively active RhoA and dominant negative RhoA inhibited wound healing, suggesting that both activation and inhibition of RhoA interfere with normal wound healing. Overexpression of wild-type Rac1 induced upregulation of RhoA, disrupted intercellular junctions, and inhibited wound closure. Dominant negative Rac1 also inhibited wound closure. Inhibition of the downstream effector of RhoA, Rho-kinase, with Y-27632 suppressed actin stress fibers and focal adhesion formation, increased Rac1 activity, and stimulated wound closure. The activity of both RhoA and Rac1 are influenced by the polymerization state of microtubules, and cell migration involves coordinated action of actin and microtubules. Microtubule depolymerization upon nocodazole treatment led to an increase in focal adhesions and decreased wound closure. We conclude that coordination of both RhoA and Rac1 activity contributes to bronchial epithelial wound repair mechanisms in vitro, that inhibition of Rho-kinase accelerates wound closure, and that efficient repair involves intact microtubules.
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Breuss, J. M., J. Gallo, H. M. DeLisser, I. V. Klimanskaya, H. G. Folkesson, J. F. Pittet, S. L. Nishimura, K. Aldape, D. V. Landers, and W. Carpenter. "Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling." Journal of Cell Science 108, no. 6 (June 1, 1995): 2241–51. http://dx.doi.org/10.1242/jcs.108.6.2241.
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The alpha v beta 6 integrin was identified in cultured epithelial cells and functions as a fibronectin receptor. We have now used monoclonal antibodies to determine in vivo expression patterns of the beta 6 subunit in normal and pathological human or primate tissues, and during experimental wound healing or induced lung injury. The results indicate that beta 6 expression is restricted to epithelia and is up-regulated in parallel with morphogenetic events, tumorigenesis, and epithelial repair. During development of the kidney, lung, and skin, we found that beta 6 is expressed by specific types of epithelial cells, whereas it is mostly undetectable in normal adult kidney, lung and skin. In contrast, we detected high-level expression in several types of carcinoma. For example, beta 6 is almost invariably neo-expressed in squamous cell carcinomas derived from the oral mucosa, often focally localized at the infiltrating edges of tumor islands. Expression of beta 6 is also upregulated in migrating keratinocytes at the wound edge during experimental epidermal wound healing. Similarly, beta 6 expression is induced in type II alveolar epithelial cells during lung injury caused by injection of live bacteria. We also observed beta 6 expression in adult lungs and kidneys at focal sites of subclinical inflammation, as well as in a variety of clinical specimens from patients with chronic or acute inflammation of the lungs or kidneys. From these findings and earlier results, we hypothesize that alpha v beta 6 affects cell spreading, migration and growth during reorganization of epithelia in development, tissue repair, and neoplasia.
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Sanders, Catherine, Shalini Sharma, Peter Vogel, Peter Doherty, and Paul Thomas. "Network analysis of lung tissue repair processes in response to influenza-induced damage identifies tissue remodeling factor TIMP-1 in recovery (P3180)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 124.1. http://dx.doi.org/10.4049/jimmunol.190.supp.124.1.
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Abstract Mild and severe influenza infections clearly differ in disease resolution, likely due to variations in the host’s repair response to lung tissue damage. Over 60 protein factors involved in lung tissue repair at multiple stages of a mild and a severe influenza infection (early, mid-stage, viral clearance, and after viral clearance) were quantified and organized into an interaction network. Factors characteristic of all phases of tissue repair—coagulation, inflammation, migration and proliferation, and remodeling—were up-regulated in mouse whole lung tissue after both types of infections. Differences in intensity and timing of these factors, particularly in the later three stages of wound repair, were observed. Network analysis allowed for identification of a key node in the repair pathway important in tissue remodeling, TIMP-1. TIMP-1-/- mice were more susceptible to PR/8 infection independently of viral titer or inflammatory immune responses. However, respiratory analyses showed exacerbated responses to both infections, suggestive of dysregulated lung function during attempted resolution of disease. We demonstrate the utility of systems biology for understanding complex, multi-layered, integrated biological processes such as wound healing, and in identification of previously overlooked factors involved in such processes. We also demonstrate the contribution of TIMP-1, a protein not involved in viral control, coagulation, or inflammation, in recovery from influenza infection.
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Zhang, Chaoqi, Lifeng Li, Kexin Feng, Daoyang Fan, Wenhua Xue, and Jingli Lu. "‘Repair’ Treg Cells in Tissue Injury." Cellular Physiology and Biochemistry 43, no. 6 (2017): 2155–69. http://dx.doi.org/10.1159/000484295.
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Studies in mice and humans have elucidated an important role for Tregs in promoting tissue repair and restoring tissue integrity. Emerging evidence has revealed that Tregs promoted wound healing and repair processes at multiple tissue sites, such as the heart, liver, kidney, muscle, lung, bone and central nervous system. The localization of repair Tregs in the lung, muscle and liver exhibited unique phenotypes and functions. Epidermal growth factor receptor, amphiregulin, CD73/CD39 and keratinocyte growth factor are important repair factors that are produced or expressed by repair Tregs; these factors coordinate with parenchymal cells to limit injury and promote repair. In addition, repair Tregs can be modulated by IL-33/ST2, TCR signals and other cytokines in the context of injured microenvironment cues. In this review, we provide an overview of the emerging knowledge about Treg-mediated repair in damaged tissues and organs.
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Trinh, Nguyen Thu Ngan, Anik Privé, Lina Kheir, Jean-Charles Bourret, Tiba Hijazi, Mohammad Gholi Amraei, Josette Noël, and Emmanuelle Brochiero. "Involvement of KATPand KvLQT1 K+channels in EGF-stimulated alveolar epithelial cell repair processes." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 4 (October 2007): L870—L882. http://dx.doi.org/10.1152/ajplung.00362.2006.
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Several respiratory diseases are associated with extensive damage of lung epithelia, and the regulatory mechanisms involved in their regeneration are not clearly defined. Growth factors released by epithelial cells or fibroblasts from injured lungs are important regulators of alveolar repair by stimulating cell motility, proliferation, and differentiation. In addition, K+channels regulate cell proliferation/migration and are coupled with growth factor signaling in several tissues. We decided to explore the hypothesis, never investigated before, that K+could play a prominent role in alveolar repair. We employed a model of mechanical wounding of rat alveolar type II epithelia, in primary culture, to study their response to injury. Wound healing was suppressed by one-half upon epidermal growth factor (EGF) titration with EGF-antibody (Ab) or erbB1/erbB2 tyrosine-kinase inhibition with AG-1478/AG-825. The addition of exogenous EGF slightly stimulated the alveolar wound healing and enhanced, by up to five times, alveolar cell migration measured in a Boyden-type chamber. Conditioned medium collected from injured alveolar monolayers also stimulated cell migration; this effect was abolished in the presence of EGF-Ab. The impact of K+channel modulators was examined in basal and EGF-stimulated conditions. Wound healing was stimulated by pinacidil, an ATP-dependent K+channel (KATP) activator, which also increased cell migration, by twofold, in basal conditions and potentiated the stimulatory effect of EGF. KATPor KvLQT1 inhibitors (glibenclamide, clofilium) reduced EGF-stimulated wound healing, cell migration, and proliferation. Finally, EGF stimulated KATPand KvLQT1 currents and channel expression. In summary, stimulation of K+channels through autocrine activation of EGF receptors could play a crucial role in lung epithelia repair processes.
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Strandjord, Thomas P., David K. Madtes, Daniel J. Weiss, and E. Helene Sage. "Collagen accumulation is decreased in SPARC-null mice with bleomycin-induced pulmonary fibrosis." American Journal of Physiology-Lung Cellular and Molecular Physiology 277, no. 3 (September 1, 1999): L628—L635. http://dx.doi.org/10.1152/ajplung.1999.277.3.l628.
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Secreted protein acidic and rich in cysteine (SPARC) has been shown to be coexpressed with type I collagen in tissues undergoing remodeling and wound repair. We speculated that SPARC is required for the accumulation of collagen in lung injury and that its absence would attenuate collagen accumulation. Accordingly, we have assessed levels of collagen in SPARC-null mice in an intratracheal bleomycin-injury model of pulmonary fibrosis. Eight- to ten-week-old SPARC-null and wild-type (WT) mice received bleomycin (0.0035 U/g) or saline intratracheally and were subsequently killed after 14 days. Relative levels of SPARC mRNA were increased 2.7-fold ( P < 0.001) in bleomycin-treated WT lungs in comparison with saline-treated lungs. Protein from bleomycin-treated WT lung contained significantly more hydroxyproline (191.9 μg/lung) than protein from either bleomycin-treated SPARC-null lungs or saline-treated WT and SPARC-null lungs (147.4 μg/lung, 125.4 μg/lung, and 113.0 μg/lung, respectively; P < 0.03). These results indicate that SPARC is increased in response to lung injury and that accumulation of collagen, as indicated by hydroxyproline content, is attenuated in the absence of SPARC. The properties of SPARC as a matricellular protein associated with cell proliferation and matrix turnover are consistent with its participation in the development of pulmonary fibrosis.
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Mihai, Cosmin, Shengying Bao, Ju-Ping Lai, Samir N. Ghadiali, and Daren L. Knoell. "PTEN inhibition improves wound healing in lung epithelia through changes in cellular mechanics that enhance migration." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 3 (February 1, 2012): L287—L299. http://dx.doi.org/10.1152/ajplung.00037.2011.
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The phosphoinositide-3 kinase/Akt pathway is a vital survival axis in lung epithelia. We previously reported that inhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a major suppressor of this pathway, results in enhanced wound repair following injury. However, the precise cellular and biomechanical mechanisms responsible for increased wound repair during PTEN inhibition are not yet well established. Using primary human lung epithelia and a related lung epithelial cell line, we first determined whether changes in migration or proliferation account for wound closure. Strikingly, we observed that cell migration accounts for the majority of wound recovery following PTEN inhibition in conjunction with activation of the Akt and ERK signaling pathways. We then used fluorescence and atomic force microscopy to investigate how PTEN inhibition alters the cytoskeletal and mechanical properties of the epithelial cell. PTEN inhibition did not significantly alter cytoskeletal structure but did result in large spatial variations in cell stiffness and in particular a decrease in cell stiffness near the wound edge. Biomechanical changes, as well as migration rates, were mediated by both the Akt and ERK pathways. Our results indicate that PTEN inhibition rapidly alters biochemical signaling events that in turn provoke alterations in biomechanical properties that enhance cell migration. Specifically, the reduced stiffness of PTEN-inhibited cells promotes larger deformations, resulting in a more migratory phenotype. We therefore conclude that increased wound closure consequent to PTEN inhibition occurs through enhancement of cell migration that is due to specific changes in the biomechanical properties of the cell.
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Crane, Meredith, Yun Xu, Sean F. Monaghan, Benjamin M. Hall, Holly L. Tran, William L. Henry, Jorge E. Albina, and Amanda M. Jamieson. "Post-traumatic pulmonary infection: the innate immune response protects the lung at the expense of the healing cutaneous wound." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 62.10. http://dx.doi.org/10.4049/jimmunol.202.supp.62.10.
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Abstract Hospitalized trauma patients have an increased risk of pulmonary infection. The acute response to injury, which relies on the coordinated activity of recruited leukocytes, may affect the early, innate immune-mediated control of lung infection. We hypothesized that a cutaneous wound would inhibit the ability of innate leukocytes to respond to a subsequent pulmonary bacterial infection. To address this, we developed a murine model of post-injury pneumonia. Mice were wounded by the dorsal subcutaneous implantation of polyvinyl alcohol sponges, which models the acute stages of wound repair, and a cohort was infected intranasally with the opportunistic bacterium Klebsiella oxytoca. For comparison, a control group was only infected. Wounding did not alter the early control of lung bacterial infection, the infiltration of innate leukocytes into the infected lung, or cytokine and chemokine levels in the bronchoalveolar lavage fluid. In contrast, pulmonary infection suppressed wound healing, caused decreased monocyte and neutrophil trafficking and lower cytokine and chemokine concentrations in the wound. Exogenous delivery of CCL2 and CXCL1 to the wound increased the number of neutrophils and accelerated healing. However, this led to increased pulmonary bacterial burden, highlighting the balance of cellular responses required to protect the lung. These data suggest that the innate immune system prioritizes the protection of one site above the other when faced with competing inflammatory insults. Here, early control of lung infection took priority over the healing wound. This work aims to elucidate mechanisms by which the innate immune system responds to multiple insults, which may be broadly applicable to inflammatory conditions.
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Rovira, I., G. Fita, A. Alcón, P. Matute, M. Iglesias, and P. Macchiarini. "Interventional lung assist (ILA) during neck wound repair after tracheal surgery: case report." European Journal of Anaesthesiology 23, Supplement 38 (May 2006): 25. http://dx.doi.org/10.1097/00003643-200605001-00071.
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Planus, E., S. Galiacy, M. Matthay, V. Laurent, J. Gavrilovic, G. Murphy, C. Clerici, D. Isabey, C. Lafuma, and M. P. d'Ortho. "Role of collagenase in mediating in vitro alveolar epithelial wound repair." Journal of Cell Science 112, no. 2 (January 15, 1999): 243–52. http://dx.doi.org/10.1242/jcs.112.2.243.
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Type II pneumocytes are essential for repair of the injured alveolar epithelium. The effect of two MMP collagenases, MMP-1 and MMP-13 on alveolar epithelial repair was studied in vitro. The A549 alveolar epithelial cell line and primary rat alveolar epithelial cell cultures were used. Cell adhesion and cell migration were measured with and without exogenous MMP-1. Wound healing of a cell monolayer of rat alveolar epithelial cell after a mechanical injury was evaluated by time lapse video analysis. Cell adhesion on type I collagen, as well as cytoskeleton stiffness, was decreased in the presence of exogenous collagenases. A similar decrease was observed when cell adhesion was tested on collagen that was first incubated with MMP-1 (versus control on intact collagen). Cell migration on type I collagen was promoted by collagenases. Wound healing of an alveolar epithelial cell monolayer was enhanced in the presence of exogenous collagenases. Our results suggest that collagenases could modulate the repair process by decreasing cell adhesion and cell stiffness, and by increasing cell migration on type I collagen. Collagen degradation could modify cell adhesion sites and collagen degradation peptides could induce alveolar type II pneumocyte migration. New insights regarding alveolar epithelial cell migration are particularly relevant to investigate early events during alveolar epithelial repair following lung injury.
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Roman, Jesse. "Fibroblasts—Warriors at the Intersection of Wound Healing and Disrepair." Biomolecules 13, no. 6 (June 6, 2023): 945. http://dx.doi.org/10.3390/biom13060945.
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Wound healing is triggered by inflammation elicited after tissue injury. Mesenchymal cells, specifically fibroblasts, accumulate in the injured tissues, where they engage in tissue repair through the expression and assembly of extracellular matrices that provide a scaffold for cell adhesion, the re-epithelialization of tissues, the production of soluble bioactive mediators that promote cellular recruitment and differentiation, and the regulation of immune responses. If appropriately deployed, these processes promote adaptive repair, resulting in the preservation of the tissue structure and function. Conversely, the dysregulation of these processes leads to maladaptive repair or disrepair, which causes tissue destruction and a loss of organ function. Thus, fibroblasts not only serve as structural cells that maintain tissue integrity, but are key effector cells in the process of wound healing. The review will discuss the general concepts about the origins and heterogeneity of this cell population and highlight the specific fibroblast functions disrupted in human disease. Finally, the review will explore the role of fibroblasts in tissue disrepair, with special attention to the lung, the role of aging, and how alterations in the fibroblast phenotype underpin disorders characterized by pulmonary fibrosis.
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Crosby, Lynn M., Charlean Luellen, Zhihong Zhang, Larry L. Tague, Scott E. Sinclair, and Christopher M. Waters. "Balance of life and death in alveolar epithelial type II cells: proliferation, apoptosis, and the effects of cyclic stretch on wound healing." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 4 (October 2011): L536—L546. http://dx.doi.org/10.1152/ajplung.00371.2010.
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After acute lung injury, repair of the alveolar epithelium occurs on a substrate undergoing cyclic mechanical deformation. While previous studies showed that mechanical stretch increased alveolar epithelial cell necrosis and apoptosis, the impact of cell death during repair was not determined. We examined epithelial repair during cyclic stretch (CS) in a scratch-wound model of primary rat alveolar type II (ATII) cells and found that CS altered the balance between proliferation and cell death. We measured cell migration, size, and density; intercellular gap formation; cell number, proliferation, and apoptosis; cytoskeletal organization; and focal adhesions in response to scratch wounding followed by CS for up to 24 h. Under static conditions, wounds were closed by 24 h, but repair was inhibited by CS. Wounding stimulated cell motility and proliferation, actin and vinculin redistribution, and focal adhesion formation at the wound edge, while CS impeded cell spreading, initiated apoptosis, stimulated cytoskeletal reorganization, and attenuated focal adhesion formation. CS also caused significant intercellular gap formation compared with static cells. Our results suggest that CS alters several mechanisms of epithelial repair and that an imbalance occurs between cell death and proliferation that must be overcome to restore the epithelial barrier.
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Slager, Rebecca E., Diane S. Allen-Gipson, Alexi Sammut, Art Heires, Jane DeVasure, Susanna Von Essen, Debra J. Romberger, and Todd A. Wyatt. "Hog barn dust slows airway epithelial cell migration in vitro through a PKCα-dependent mechanism." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 6 (December 2007): L1469—L1474. http://dx.doi.org/10.1152/ajplung.00274.2007.
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Agricultural work and other occupational exposures are responsible for ∼15% of chronic obstructive pulmonary disease (COPD). COPD involves airway remodeling in response to chronic lung inflammatory events and altered airway repair mechanisms. However, the effect of agricultural dust exposure on signaling pathways that regulate airway injury and repair has not been well characterized. A key step in this process is migration of airway cells to restore epithelial integrity. We have previously shown that agents that activate the critical regulatory enzyme protein kinase C (PKC) slow cell migration during wound repair. Based on this observation and direct kinase measurements that demonstrate that dust extract from hog confinement barns (HDE) specifically activates the PKC isoforms PKCα and PKCε, we hypothesized that HDE would slow wound closure time in airway epithelial cells. We utilized the human bronchial epithelial cell line BEAS-2B and transfected BEAS-2B cell lines that express dominant negative (DN) forms of PKC isoforms to demonstrate that HDE slows wound closure in BEAS-2B and PKCε DN cell lines. However, in PKCα DN cells, wound closure following HDE treatment is not significantly different than media-treated cells. These results suggest that the PKCα isoform is an important regulator of cell migration in response to agricultural dust exposure.
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Ishida, Yuko, Yumi Kuninaka, Naofumi Mukaida, and Toshikazu Kondo. "Immune Mechanisms of Pulmonary Fibrosis with Bleomycin." International Journal of Molecular Sciences 24, no. 4 (February 5, 2023): 3149. http://dx.doi.org/10.3390/ijms24043149.
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Fibrosis and structural remodeling of the lung tissue can significantly impair lung function, often with fatal consequences. The etiology of pulmonary fibrosis (PF) is diverse and includes different triggers such as allergens, chemicals, radiation, and environmental particles. However, the cause of idiopathic PF (IPF), one of the most common forms of PF, remains unknown. Experimental models have been developed to study the mechanisms of PF, and the murine bleomycin (BLM) model has received the most attention. Epithelial injury, inflammation, epithelial–mesenchymal transition (EMT), myofibroblast activation, and repeated tissue injury are important initiators of fibrosis. In this review, we examined the common mechanisms of lung wound-healing responses after BLM-induced lung injury as well as the pathogenesis of the most common PF. A three-stage model of wound repair involving injury, inflammation, and repair is outlined. Dysregulation of one or more of these three phases has been reported in many cases of PF. We reviewed the literature investigating PF pathogenesis, and the role of cytokines, chemokines, growth factors, and matrix feeding in an animal model of BLM-induced PF.
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Desai, Leena P., Kenneth E. Chapman, and Christopher M. Waters. "Mechanical stretch decreases migration of alveolar epithelial cells through mechanisms involving Rac1 and Tiam1." American Journal of Physiology-Lung Cellular and Molecular Physiology 295, no. 5 (November 2008): L958—L965. http://dx.doi.org/10.1152/ajplung.90218.2008.
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Mechanical ventilation can overdistend the lungs or generate shear forces in them during repetitive opening/closing, contributing to lung injury and inflammation in patients with acute respiratory distress syndrome (ARDS). Repair of the injured lung epithelium is important for restoring normal barrier and lung function. In the current study, we investigated the effects of cyclic mechanical strain (CS), constant distention strain (CD), and simulated positive end-expiratory pressure (PEEP) on activation of Rac1 and wound closure of rat primary alveolar type 2 (AT2) cells. Cyclic stretch inhibited the migration of wounded AT2 cells in a dose-dependent manner with no inhibition occurring with 5% CS, but significant inhibition with 10% and 15% CS. PEEP conditions were investigated by stretching AT2 cells to 15% maximum strain (at a frequency of 10 cycles/min) with relaxation to 10% strain. AT2 cells were also exposed to 20% CD. All three types of mechanical strain inhibited wound closure of AT2 cells compared with static controls. Since lamellipodial extensions in migrating cells at the wound edge were significantly smaller in stretched cells, we measured Rac1 activity and found it to be decreased in stretched cells. We also demonstrate that Tiam1, a Rac1-specific guanine nucleotide exchange factor, was expressed mainly in the cytosol of AT2 cells exposed to mechanical strain compared with membrane localization in static cells. Downregulation of Tiam1 with 100 μM NSC-23766 inhibited activation of Rac1 and migration of AT2 cells, suggesting its involvement in repair mechanisms of AT2 cells subjected to mechanical strain.
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Ochoa, Carmen A., Claire G. Nissen, Deanna D. Mosley, Christopher D. Bauer, Destiny L. Jordan, Kristina L. Bailey, and Todd A. Wyatt. "Aldehyde Trapping by ADX-102 Is Protective against Cigarette Smoke and Alcohol Mediated Lung Cell Injury." Biomolecules 12, no. 3 (March 2, 2022): 393. http://dx.doi.org/10.3390/biom12030393.
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Most individuals diagnosed with alcohol use disorders smoke cigarettes. Large concentrations of malondialdehyde and acetaldehyde are found in lungs co-exposed to cigarette smoke and alcohol. Aldehydes directly injure lungs and form aldehyde protein adducts, impacting epithelial functions. Recently, 2-(3-Amino-6-chloroquinolin-2-yl)propan-2-ol (ADX-102) was developed as an aldehyde-trapping drug. We hypothesized that aldehyde-trapping compounds are protective against lung injury derived from cigarette smoke and alcohol co-exposure. To test this hypothesis, we pretreated mouse ciliated tracheal epithelial cells with 0–100 µM of ADX-102 followed by co-exposure to 5% cigarette smoke extract and 50 mM of ethanol. Pretreatment with ADX-102 dose-dependently protected against smoke and alcohol induced cilia-slowing, decreases in bronchial epithelial cell wound repair, decreases in epithelial monolayer resistance, and the formation of MAA adducts. ADX-102 concentrations up to 100 µM showed no cellular toxicity. As protein kinase C (PKC) activation is a known mechanism for slowing cilia and wound repair, we examined the effects of ADX-102 on smoke and alcohol induced PKC epsilon activity. ADX-102 prevented early (3 h) activation and late (24 h) autodownregulation of PKC epsilon in response to smoke and alcohol. These data suggest that reactive aldehydes generated from cigarette smoke and alcohol metabolism may be potential targets for therapeutic intervention to reduce lung injury.
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Kim, Sang Yong, Jiang Li, Abigail C. Burr, Hashini Batugedara, Tara Nordgren, Xingxing Zang, and Meera G. Nair. "Resistin-like molecule alpha (RELMα) dampens lung inflammation and promotes wound healing in helminth infection and a 3D lung repair model." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 185.9. http://dx.doi.org/10.4049/jimmunol.202.supp.185.9.
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Abstract RELMα is a small secreted and immunoregulatory protein, also known as hypoxia-induced mitogenic factor (HIMF) and found in inflammatory zone (FIZZ). RELMα, produced by macrophages and epithelial cells in the lung and intestine, has recently been shown by our lab and others to induce wound healing during Nippostrongylus brasiliensis (Nb) infection. However, the mechanisms by which RELMα activates wound healing pathways and what cell-types are activated by RELMα are unclear. We generated constitutive RELMα−/−/TdTomato-red (TdT) reporter mice to delete the RELMα gene and track RELMα promoter activity. We found that following Nb infection, RELMα−/− macrophages exhibited reduced expression of genes associated with wound healing such as Arg1, Mmp19 and Pdgfra. To complement the RELMα−/− mouse in vivo studies, a new endotoxin-free RELMα-human Fc fusion protein was constructed and purified. A RELMα capture assay with the fusion protein demonstrated that RELMα binds to macrophage cell line RAW 264.7. Moreover, 3D lung scaffold and wound healing assays showed that RELMα-Fc promoted tissue repair by lung epithelial cells and mesenchymal stem cells. Lastly, RELMα function in vivo was characterized by RELMα-Fc fusion protein treatment of Nb-infected RELMα−/−/TdT mice, which downregulated immune cell recruitment in the lung compared to control Fc. Ongoing studies include identification of the RELMα receptor using the RELMα fusion proteins and testing whether the wound healing properties of RELMα are effective in the intestine following Heligosomoides polygyrus infection.
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Nordgren, Tara M., Art J. Heires, Kristina L. Bailey, Dawn M. Katafiasz, Myron L. Toews, Christopher S. Wichman, and Debra J. Romberger. "Docosahexaenoic acid enhances amphiregulin-mediated bronchial epithelial cell repair processes following organic dust exposure." American Journal of Physiology-Lung Cellular and Molecular Physiology 314, no. 3 (March 1, 2018): L421—L431. http://dx.doi.org/10.1152/ajplung.00273.2017.
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Injurious dust exposures in the agricultural workplace involve the release of inflammatory mediators and activation of epidermal growth factor receptor (EGFR) in the respiratory epithelium. Amphiregulin (AREG), an EGFR ligand, mediates tissue repair and wound healing in the lung epithelium. Omega-3 fatty acids such as docosahexaenoic acid (DHA) are also known modulators of repair and resolution of inflammatory injury. This study investigated how AREG, DHA, and EGFR modulate lung repair processes following dust-induced injury. Primary human bronchial epithelial (BEC) and BEAS-2B cells were treated with an aqueous extract of swine confinement facility dust (DE) in the presence of DHA and AREG or EGFR inhibitors. Mice were exposed to DE intranasally with or without EGFR inhibition and DHA. Using a decellularized lung scaffolding tissue repair model, BEC recolonization of human lung scaffolds was analyzed in the context of DE, DHA, and AREG treatments. Through these investigations, we identified an important role for AREG in mediating BEC repair processes. DE-induced AREG release from BEC, and DHA treatment following DE exposure, enhanced this release. Both DHA and AREG also enhanced BEC repair capacities and rescued DE-induced recellularization deficits. In vivo, DHA treatment enhanced AREG production following DE exposure, whereas EGFR inhibitor-treated mice exhibited reduced AREG in their lung homogenates. These data indicate a role for AREG in the process of tissue repair after inflammatory lung injury caused by environmental dust exposure and implicate a role for DHA in regulating AREG-mediated repair signaling in BEC.
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Leer, Coretta Van, Monika Stutz, André Haeberli, and Thomas Geiser. "Urokinase plasminogen activator released by alveolar epithelial cells modulates alveolar epithelial repair in vitro." Thrombosis and Haemostasis 94, no. 12 (2005): 1257–64. http://dx.doi.org/10.1160/th05-03-0162.
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SummaryIntra-alveolar fibrin is formed following lung injury and inflammation and may contribute to the development of pulmonary fibrosis. Fibrin turnover is altered in patients with pulmonary fibrosis, resulting in intra-alveolar fibrin accumulation, mainly due to decreased fibrinolysis. Alveolar type II epithelial cells (AEC) repair the injured alveolar epithelium by migrating over the provisional fibrin matrix. We hypothesized that repairing alveolar epithelial cells modulate the underlying fibrin matrix by release of fibrinolytic activity, and that the degree of fibrinolysis modulates alveolar epithelial repair on fibrin. To test this hypothesis we studied alveolar epithelial wound repair in vitro using a modified epithelial wound repair model with human A549 alveolar epithelial cells cultured on a fibrin matrix. In presence of the inflammatory cytokine interleukin-1β, wounds increase by 800% in 24 hours mainly due to detachment of the cells, whereas in serum-free medium wound areas decreases by 22.4 ± 5.2 % (p<0.01). Increased levels of D-dimer, FDP and uPA in the cell supernatant of IL-1β-stimulated A549 epithelial cells indicate activation of fibrinolysis by activation of the plasmin system. In presence of low concentrations of fibrinolysis inhibitors, including specific blocking anti-uPA antibodies, alveolar epithelial repair in vitro was improved, whereas in presence of high concentrations of fibrinolysis inhibitors, a decrease was observed mainly due to decreased spreading and migration of cells. These findings suggest the existence of a fibrinolytic optimum at which alveolar epithelial repair in vitro is most efficient. In conclusion, uPA released by AEC alters alveolar epithelial repair in vitro by modulating the underlying fibrin matrix.
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Su, Yunchao, Wengang Cao, Zhaosheng Han, and Edward R. Block. "Cigarette smoke extract inhibits angiogenesis of pulmonary artery endothelial cells: the role of calpain." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 4 (October 2004): L794—L800. http://dx.doi.org/10.1152/ajplung.00079.2004.
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Angiogenesis is an integral part of both the pulmonary inflammatory response to chronic exposure to cigarette smoke and the lung tissue remodeling associated with cigarette smoke-induced chronic obstructive pulmonary disease (COPD). To investigate the role of angiogenesis in the pathogenesis of COPD, we evaluated the effect of cigarette smoke extract (CSE) on angiogenesis of pulmonary artery endothelial cells (PAEC). Incubation of PAEC with 2.5–10% CSE resulted in a dose-dependent inhibition of endothelial monolayer wound repair. CSE also caused inhibition of tube formation on Matrigel, migration in a Boyden chamber, and proliferation of PAEC. Because calpain, a family of calcium-dependent intracellular proteases, mediates cytoskeletal signaling in endothelial motility, we explored the role of calpain in the CSE-induced inhibition of endothelial angiogenesis. Incubation of CSE resulted in a dose-dependent decrease in calpain activity. Calpain inhibitor-1, a specific inhibitor of calpain, potentiates inhibitory effect of CSE on the endothelial monolayer wound repair, tube formation, cell migration, and cell proliferation. Transfection of PAEC with antisense oligodeoxyribonucleotides of calpastatin, the major endogenous calpain inhibitor, prevented CSE-induced increase in calpastatin protein content and CSE-induced decreases in calpain activity. It also prevented CSE-induced decreases in monolayer wound repair, tube formation, and migration. These results suggest that CSE attenuates angiogenesis of PAEC and the mechanism involves inhibition of calpain. Impaired angiogenesis may impede the repair process in the lungs of cigarette smokers and contribute to the altered structural remodeling observed in the lungs of patients with cigarette smoke-related COPD.
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Howat, William J., Stephen T. Holgate, and Peter M. Lackie. "TGF-β isoform release and activation during in vitro bronchial epithelial wound repair." American Journal of Physiology-Lung Cellular and Molecular Physiology 282, no. 1 (January 1, 2002): L115—L123. http://dx.doi.org/10.1152/ajplung.2002.282.1.l115.
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Restitution of an epithelial layer after environmental or biological damage is important to maintain the normal function of the respiratory tract. We have investigated the role of transforming growth factor (TGF)-β isoforms in the repair of layers of 16HBE 14o− bronchial epithelial-derived cells after damage by multiple scoring. ELISA showed that both latent TGF-β1 and TGF-β2 were converted to their active forms 2 h after wounding. Time-lapse microscopy showed that the addition of TGF-β1, but not TGF-β2, progressively increased the rate of migration of damaged monolayers at concentrations down to 250 pg/ml. This increase was blocked by addition of a neutralizing TGF-β1 antibody. Phase-contrast microscopy and inhibition of proliferation with mitomycin C showed that proliferation was not required for migration. These results demonstrate that conversion of latent to active TGF-β1 and TGF-β2 during in vitro epithelial wound repair occurs quickly and that TGF-β1 speeds epithelial repair. A faster repair may be advantageous in preventing access of environmental agents to the internal milieu of the lung although the production of active TGF-β molecules may augment subepithelial fibrosis.
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Eckhardt, Christina M., and Haotian Wu. "Environmental Exposures and Lung Aging: Molecular Mechanisms and Implications for Improving Respiratory Health." Current Environmental Health Reports 8, no. 4 (November 4, 2021): 281–93. http://dx.doi.org/10.1007/s40572-021-00328-2.
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Abstract Purpose of Review Inhaled environmental exposures cause over 12 million deaths per year worldwide. Despite localized efforts to reduce environmental exposures, tobacco smoking and air pollution remain the urgent public health challenges that are contributing to the growing prevalence of respiratory diseases. The purpose of this review is to describe the mechanisms through which inhaled environmental exposures accelerate lung aging and cause overt lung disease. Recent Findings Environmental exposures related to fossil fuel and tobacco combustion and occupational exposures related to silica and coal mining generate oxidative stress and inflammation in the lungs. Sustained oxidative stress causes DNA damage, epigenetic instability, mitochondrial dysfunction, and cell cycle arrest in key progenitor cells in the lung. As a result, critical repair mechanisms are impaired, leading to premature destruction of the lung parenchyma. Summary Inhaled environmental exposures accelerate lung aging by injuring the lungs and damaging the cells responsible for wound healing. Interventions that minimize exposure to noxious antigens are critical to improve lung health, and novel research is required to expand our knowledge of therapies that may slow or prevent premature lung aging.
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Ndiaye, Assane, Magaye Gaye, Papa Salmane Ba, Souleymane Diatta, Momar Sokhna Diop, and Mouhamadou Ndiaye. "Penetrating chest injuries caused by swordfish sword used as a weapon." Asian Cardiovascular and Thoracic Annals 25, no. 3 (February 10, 2017): 229–32. http://dx.doi.org/10.1177/0218492317694521.
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We report 5 cases of penetrating chest wounds caused by weapons made from swordfish swords, involving breakage of the sword that later appeared as a thoracic foreign body. The patients had been assaulted 2 days to 17 years earlier. Three of them had a chronic infected wound, one had a penetrating thoracic wound with hemopneumothorax, and one had a foreign body. Computed tomography showed a foreign body in the lung in 4 cases, with aortic penetration in one. The foreign body was removed via thoracotomy in all 4 patients, with aorta repair in one who presented later with a pseudoaneurysm.
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Ku, Hui-Chun, Shih-Yi Lee, Yung-Kai Lin, Yung-Hsiang Lin, and Chi-Fu Chiang. "Protective effects of Mosla Chinensis Maxim against Lung Injury." Scholars Academic Journal of Biosciences 11, no. 11 (November 24, 2023): 389–96. http://dx.doi.org/10.36347/sajb.2023.v11i11.004.
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Lung fibrosis is a common form of interstitial lung disease. Traditional Chinese medicinal plants have the ability to suppress lung inflammation, but there are relatively few studies on the relationship between Mosla Chinensis Maxim and lung injury. The purpose of this study was to investigate whether Mosla Chinensis Maxim extract (MCME) can alleviate lung injury. This study utilized lung epithelial cells, A549, treated MCME (0.25mg/mL), and analyzed the wound-healing ability, inflammatory cytokines, and cell-cell adheren junctions (E-cadherin). Bleomycin was used to induced lung fibrosis in an animal model, which were then treated with MCME. The results showed that MCME improved cellular repair capacity by 30% compared to the mock group, inhibited IL-8 by approximately 60%, and increased the E-cadherin expression compared to the lipopolysaccharide group. In an animal model, administration of MCME (50 mg/kg) for 14 days alleviated the bleomycin-induced pathological changes in the lungs and fibrosis. This study demonstrated that MCME improved lung injury.
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Wright, Ciara, Ruth Pilkington, Máire Callaghan, and Siobhán McClean. "Activation of MMP-9 by human lung epithelial cells in response to the cystic fibrosis-associated pathogen Burkholderia cenocepacia reduced wound healing in vitro." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 4 (October 2011): L575—L586. http://dx.doi.org/10.1152/ajplung.00226.2010.
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Burkholderia cepacia complex is a group of bacterial pathogens that cause opportunistic infections in cystic fibrosis (CF). The most virulent of these is Burkholderia cenocepacia . Matrix metalloproteinases (MMPs) are upregulated in CF patients. The aim of this work was to examine the role of MMPs in the pathogenesis of B. cepacia complex, which has not been explored to date. Real-time PCR analysis showed that B. cenocepacia infection upregulated MMP-2 and MMP-9 genes in the CF lung cell line CFBE41o− within 1 h, whereas MMP-2, -7, and -9 genes were upregulated in the non-CF lung cell line 16HBE14o−. Conditioned media from both cell lines showed increased MMP-9 activation following B. cenocepacia infection. Conditioned media from B. cenocepacia -infected cells significantly reduced the rate of wound healing in confluent lung epithelia ( P < 0.05), in contrast to conditioned media from Pseudomonas aeruginosa -infected cells, which showed predominant MMP-2 activation. Treatment of control conditioned media from both cell lines with the MMP activator 4-aminophenylmercuric acetate (APMA) also resulted in clear activation of MMP-9 and to a much lesser extent MMP-2. APMA treatment of control media also delayed the repair of wound healing in confluent epithelial cells. Furthermore, specific inhibition of MMP-9 in medium from cells exposed to B. cenocepacia completely reversed the delay in wound repair. These data suggest that MMP-9 plays a role in the reduced epithelial repair observed in response to B. cenocepacia infection and that its activation following B. cenocepacia infection contributes to the pathogenesis of this virulent pathogen.
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Sun, Zhenghua, Hao Xiong, Tengfei Lou, Weixuan Liu, Yi Xu, Shiyang Yu, Hui Wang, et al. "Multifunctional Extracellular Matrix Hydrogel with Self-Healing Properties and Promoting Angiogenesis as an Immunoregulation Platform for Diabetic Wound Healing." Gels 9, no. 5 (May 5, 2023): 381. http://dx.doi.org/10.3390/gels9050381.
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Treating chronic wounds is a global challenge. In diabetes mellitus cases, long-time and excess inflammatory responses at the injury site may delay the healing of intractable wounds. Macrophage polarization (M1/M2 types) can be closely associated with inflammatory factor generation during wound healing. Quercetin (QCT) is an efficient agent against oxidation and fibrosis that promotes wound healing. It can also inhibit inflammatory responses by regulating M1-to-M2 macrophage polarization. However, its limited solubility, low bioavailability, and hydrophobicity are the main issues restricting its applicability in wound healing. The small intestinal submucosa (SIS) has also been widely studied for treating acute/chronic wounds. It is also being extensively researched as a suitable carrier for tissue regeneration. As an extracellular matrix, SIS can support angiogenesis, cell migration, and proliferation, offering growth factors involved in tissue formation signaling and assisting wound healing. We developed a series of promising biosafe novel diabetic wound repair hydrogel wound dressings with several effects, including self-healing properties, water absorption, and immunomodulatory effects. A full-thickness wound diabetic rat model was constructed for in vivo assessment of QCT@SIS hydrogel, in which hydrogels achieved a markedly increased wound repair rate. Their effect was determined by the promotion of the wound healing process, the thickness of granulation tissue, vascularization, and macrophage polarization during wound healing. At the same time, we injected the hydrogel subcutaneously into healthy rats to perform histological analyses of sections of the heart, spleen, liver, kidney, and lung. We then tested the biochemical index levels in serum to determine the biological safety of the QCT@SIS hydrogel. In this study, the developed SIS showed convergence of biological, mechanical, and wound-healing capabilities. Here, we focused on constructing a self-healing, water-absorbable, immunomodulatory, and biocompatible hydrogel as a synergistic treatment paradigm for diabetic wounds by gelling the SIS and loading QCT for slow drug release.
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Horie, Shahd, Hector Gonzalez, Jack Brady, James Devaney, Michael Scully, Daniel O’Toole, and John G. Laffey. "Fresh and Cryopreserved Human Umbilical-Cord-Derived Mesenchymal Stromal Cells Attenuate Injury and Enhance Resolution and Repair following Ventilation-Induced Lung Injury." International Journal of Molecular Sciences 22, no. 23 (November 27, 2021): 12842. http://dx.doi.org/10.3390/ijms222312842.
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Background: Ventilator-induced lung injury (VILI) frequently worsens acute respiratory distress syndrome (ARDS) severity. Human mesenchymal stem/stromal cells (MSCs) offer considerable therapeutic promise, but the key impediments of clinical translation stem from limitations due to cell source and availability, and concerns regarding the loss of efficacy following cryopreservation. These experiments compared the efficacy of umbilical-cord-derived MSCs (UC-MSCs), a readily available and homogenous tissue source, to the previously more widely utilised bone-marrow-derived MSCs (BM-MSCs). We assessed their capacity to limit inflammation, resolve injury and enhance repair in relevant lung mechanical stretch models, and the impact of cryopreservation on therapeutic efficacy. Methods: In series 1, confluent alveolar epithelial layers were subjected to cyclic mechanical stretch (22% equibiaxial strain) and wound injury, and the potential of the secretome from BM- and UC-derived MSCs to attenuate epithelial inflammation and cell death, and enhance wound repair was determined. In series 2, anesthetized rats underwent VILI, and later received, in a randomised manner, 1 × 107 MSCs/kg intravenously, that were: (i) fresh BM-MSCs, (ii) fresh UC-MSCs or (iii) cryopreserved UC-MSCs. Control animals received a vehicle (PBS). The extent of the resolution of inflammation and injury, and repair was measured at 24 h. Results: Conditioned medium from BM-MSCs and UC-MSCs comparably decreased stretch-induced pulmonary epithelial inflammation and cell death. BM-MSCs and UC-MSCs comparably enhanced wound resolution. In animals subjected to VILI, both fresh BM-MSCs and UC-MSCs enhanced injury resolution and repair, while cryopreserved UC-MSCs comparably retained their efficacy. Conclusions: Cryopreserved UC-MSCs can reduce stretch-induced inflammation and cell death, enhance wound resolution, and enhance injury resolution and repair following VILI. Cryopreserved UC-MSCs represent a more abundant, cost-efficient, less variable and equally efficacious source of therapeutic MSC product.
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Wang, Huafang, and Yunchao Su. "Collagen IV contributes to nitric oxide-induced angiogenesis of lung endothelial cells." American Journal of Physiology-Cell Physiology 300, no. 5 (May 2011): C979—C988. http://dx.doi.org/10.1152/ajpcell.00368.2010.
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Nitric oxide (NO) mediates endothelial angiogenesis via inducing the expression of integrin αvβ3. During angiogenesis, endothelial cells adhere to and migrate into the extracellular matrix through integrins. Collagen IV binds to integrin αvβ3, leading to integrin activation, which affects a number of signaling processes in endothelial cells. In the present study, we evaluated the role of collagen IV in NO-induced angiogenesis. We found that NO donor 2,2′-(hydroxynitrosohydrazino)bis-ethanamine (NOC-18) causes increases in collagen IV mRNA and protein in lung endothelial cells and collagen IV release into the medium. Addition of collagen IV into the coating of endothelial culture increases endothelial monolayer wound repair, proliferation, and tube formation. Inhibition of collagen IV synthesis using gene silencing attenuates NOC-18-induced increases in monolayer wound repair, cell proliferation, and tube formation as well as in the phosphorylation of focal adhesion kinase (FAK). Integrin blocking antibody LM609 prevents NOC-18-induced increase in endothelial monolayer wound repair. Inhibition of protein kinase G (PKG) using the specific PKG inhibitor KT5823 or PKG small interfering RNA prevents NOC-18-induced increases in collagen IV protein and mRNA and endothelial angiogenesis. Together, these results indicate that NO promotes collagen IV synthesis via a PKG signaling pathway and that the increase in collagen IV synthesis contributes to NO-induced angiogenesis of lung endothelial cells through integrin-FAK signaling. Manipulation of collagen IV could be a novel approach for the prevention and treatment of diseases such as alveolar capillary dysplasia, severe pulmonary arterial hypertension, and tumor invasion.
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Florez-Sampedro, Laura, Shanshan Song, and Barbro N. Melgert. "The diversity of myeloid immune cells shaping wound repair and fibrosis in the lung." Regeneration 5, no. 1 (February 23, 2018): 3–25. http://dx.doi.org/10.1002/reg2.97.
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Linfield, Debra T., Nannan Gao, Andjela Raduka, Terri J. Harford, Giovanni Piedimonte, and Fariba Rezaee. "RSV attenuates epithelial cell restitution by inhibiting actin cytoskeleton-dependent cell migration." American Journal of Physiology-Lung Cellular and Molecular Physiology 321, no. 1 (July 1, 2021): L189—L203. http://dx.doi.org/10.1152/ajplung.00118.2021.
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The airway epithelium’s ability to repair itself after injury, known as epithelial restitution, is an essential mechanism enabling the respiratory tract’s normal functions. Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections worldwide. We sought to determine whether RSV delays the airway epithelium wound repair process both in vitro and in vivo. We found that RSV infection attenuated epithelial cell migration, a step in wound repair, promoted stress fiber formation, and mediated assembly of large focal adhesions. Inhibition of Rho-associated kinase, a master regulator of actin function, reversed these effects. There was increased RhoA and phospho-myosin light chain 2 following RSV infection. In vivo, mice were intraperitoneally inoculated with naphthalene to induce lung injury, followed by RSV infection. RSV infection delayed reepithelialization. There were increased concentrations of phospho-myosin light chain 2 in day 7 naphthalene + RSV animals, which normalized by day 14. This study suggests a key mechanism by which RSV infection delays wound healing.
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González-López, Adrián, Aurora Astudillo, Emilio García-Prieto, María Soledad Fernández-García, Antonio López-Vázquez, Estefanía Batalla-Solís, Francisco Taboada, Antonio Fueyo, and Guillermo M. Albaiceta. "Inflammation and matrix remodeling during repair of ventilator-induced lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 4 (October 2011): L500—L509. http://dx.doi.org/10.1152/ajplung.00010.2011.
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High-pressure ventilation triggers different inflammatory and matrix remodeling responses within the lung. Although some of them may cause injury, the involvement of these mediators in repair is largely unknown. To identify mechanisms of repair after ventilator-induced lung injury (VILI), mice were randomly assigned to baseline conditions (no ventilation), injury [90 min of high-pressure ventilation without positive end-expiratory pressure (PEEP)], repair (injury followed by 4 h of low-pressure ventilation with PEEP), and ventilated controls (low-pressure ventilation with PEEP for 90 and 330 min). Histological injury and lung permeability increased during injury, but were partially reverted in the repair group. This was accompanied by a proinflammatory response, together with increases in TNF-α and IFN-γ, which returned to baseline during repair, and a decrease in IL-10. However, macrophage inflammatory protein-2 (MIP-2) and matrix metalloproteinases (MMP)-2 and -9 increased after injury and persisted in being elevated during repair. Mortality in the repair phase was 50%. Survivors showed increased cell proliferation, lower levels of collagen, and higher levels of MIP-2 and MMP-2. Pan-MMP or specific MMP-2 inhibition (but not MIP-2, TNF-α, or IL-4 inhibition) delayed epithelial repair in an in vitro wound model using murine or human alveolar cells cultured in the presence of bronchoalveolar lavage fluid from mice during the repair phase or from patients with acute respiratory distress syndrome, respectively. Similarly, MMP inhibition with doxycycline impaired lung repair after VILI in vivo. In conclusion, VILI can be reverted by normalizing ventilation pressures. An adequate inflammatory response and extracellular matrix remodeling are essential for recovery. MMP-2 could play a key role in epithelial repair after VILI and acute respiratory distress syndrome.
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Tong, Yilan, Sijiong Yu, Kaijun Guo, Xiangsheng Wang, Yang Wu, Zhongyuan Xia, Guang Li, Haifeng Hu, Mosheng Yu, and Zhanyong Zhu. "First known case of successful pressure ulcer treatment in a lung transplant patient with post-COVID-19 pneumonia." Journal of Wound Care 30, no. 8 (August 2, 2021): 594–97. http://dx.doi.org/10.12968/jowc.2021.30.8.594.
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Given the current COVID-19 crisis, multiple clinical manifestations and related complications of COVID-19 disease, especially in lung transplant patients following post-COVID-19 pneumonia, are a major challenge. Herein, we report the therapeutic course of the first reported case of sacrococcyx pressure ulcers (PU) in a 65-year-old male COVID-19 patient who underwent lung transplantation and developed a PU following surgery. We used a combination of regulated negative pressure-assisted wound therapy system (RNPT, six treatment courses, five days per treatment course), a skin tension-relief system (an intraoperative aid in minimising wounds caused by sacrococcygeal PUs) and a gluteus maximus myocutaneous flap to repair sacrococcygeal wounds. This successfully treated case provides a reference point for the treatment of similar cases.
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Reynolds, Susan D., Hongmei Shen, Paul R. Reynolds, Tomoko Betsuyaku, Joseph M. Pilewski, Federica Gambelli, Michelangelo DeGuiseppe, Luis A. Ortiz, and Barry R. Stripp. "Molecular and functional properties of lung SP cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 4 (April 2007): L972—L983. http://dx.doi.org/10.1152/ajplung.00090.2006.
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Previous analysis of lung injury and repair has provided evidence for region-specific stem cells that maintain proximal and distal epithelial compartments. However, redundant expression of lineage markers by cells at several levels of the stem cell hierarchy has complicated phenotypic and functional characterization of clonogenic airway cells. Based on the demonstration that rapid efflux of the DNA dye Hoechst 33342 can be used to prospectively purify long-term repopulating hematopoietic stem cells, we hypothesized that lung cells with similar biochemical properties would be enriched for clonogenic progenitors. We demonstrate that Hoechst-dim side population (SP) cells isolated from proximal and distal compartments of the mouse lung were relatively small and agranular, exhibited low red and green autofluorescence, and that the SP fraction was highly enriched in clonogenic cells. Quantitative RT-PCR indicated that vimentin mRNA was enriched and that epithelial markers were depleted in these preparations of SP cells. Bleomycin exposure was associated with decreased clonogenicity among alveolar SP and suggested that SP cell function was compromised under profibrotic conditions. We conclude that the SP phenotype is common to clonogenic cells at multiple airway locations and suggest that Hoechst efflux is a property of cells expressing a wound-repair phenotype.
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Chen, Fei, Zhugong Liu, Qian Liu, Wenhui Wu, Scott Bowdridge, Ariel Millman, Cristina Rozo, and William Gause. "IL-4Rα signaling may enhance resolution of parasite-induced lung damage by inhibiting inflammation and mediating acute wound healing (37.8)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 37.8. http://dx.doi.org/10.4049/jimmunol.184.supp.37.8.
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Abstract The parasitic nematode Nippostrongylus brasiliensis (Nb) third-stage larvae (L3) migrate to the host lung at about 24 to 48 hrs after infection, causing lung damage, inflammation and a potent Th2-type response. Yet, little is known about the mechanism causing lung damage and whether components of the Th2-type immune response contribute to acute lung wound repair. In this study we report that migrating Nb larvae (L3) induce lung inflammation that results in increased hemorrhaging in addition to mechanical damage in the lung. Neutrophil depletion reduced lung hemorrhage and both hemorrhaging and neutrophil infiltration were decreased in Nb-infected IL-17R KO mice. Resolution of acute hemorrhage and inflammation was dependent on either IL-4 or IL-13 as IL-4Rα KO mice, but not IL-13Rα or IL-4 deficient mice, induced significantly higher hemorrhaging, neutrophil influx, and IL-17 expression. Elevations in Arg1, IGF-1, and IL-10 were also inhibited in IL-4RαKO mice. In IL-10KO mice, resolution of inflammation was also blocked, control of hemorrhaging was partly suppressed, and Arg1 and IGF-1 elevations were not affected. These data suggest that the Th2-type immune response mediates acute wound healing and control of IL-17-dependent inflammation during helminth infection.
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Mok, Pooi Ling, Arun Neela Kumar Anandasayanam, Hernandez Maradiaga Oscar David, Jiabei Tong, Aisha Farhana, Mohammed Safwan Ali Khan, Gothai Sivaprakasam, Avin Ee-Hwan Koh, and Badr Alzahrani. "Lung development, repair and cancer: A study on the role of MMP20 gene in adenocarcinoma." PLOS ONE 16, no. 4 (April 29, 2021): e0250552. http://dx.doi.org/10.1371/journal.pone.0250552.
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Multiple matrix metalloproteinases have significant roles in tissue organization during lung development, and repair. Imbalance of proteinases may lead to chronic inflammation, changes in tissue structure, and are also highly associated to cancer development. The role of MMP20 is not well studied in lung organogenesis, however, it was previously shown to be present at high level in lung adenocarcinoma. The current study aimed to identify the functional properties of MMP20 on cell proliferation and motility in a lung adenocarcinoma in vitro cell model, and relate the interaction of MMP20 with other molecular signalling pathways in the lung cells after gaining tumoral properties. In this study, two different single guide RNA (sgRNAs) that specifically targeted on MMP20 sites were transfected into human lung adenocarcinoma A549 cells by using CRISPR-Cas method. Following that, the changes of PI3-K, survivin, and MAP-K mRNA gene expression were determined by Real-Time Polymerase Chain Reaction (RT-PCR). The occurrence of cell death was also examined by Acridine Orange/Propidium Iodide double staining. Meanwhile, the motility of the transfected cells was evaluated by wound healing assay. All the data were compared with non-transfected cells as a control group. Our results demonstrated that the transfection of the individual sgRNAs significantly disrupted the proliferation of the A549 cell line through suppression in the gene expression of PI3-K, survivin, and MAP-K. When compared to non-transfected cells, both experimental cell groups showed reduction in the migration rate, as reflected by the wider gaps in the wound healing assay. The current study provided preliminary evidence that MMP20 could have regulatory role on stemness and proliferative genes in the lung tissues and affect the cell motility. It also supports the notion that targeting MMP20 could be a potential treatment mode for halting cancer progression.