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Airway Fibrosis (airway + fibrosis)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

MMP-Dependent Migration of Extrapulmonary Myofibroblast Progenitors Contributing to Posttransplant Airway Fibrosis in the Lung

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009
M. Sato
Myofibroblasts play a central role in fibroproliferative airway remodeling in obliterative bronchiolitis (OB) after lung transplantation. The purpose of the study is to elucidate the mechanisms whereby matrix metalloproteinases (MMPs) contribute to myofibroblast-mediated allograft airway fibrosis. In an intrapulmonary tracheal transplant model of OB, broad-spectrum MMP inhibitors, SC080 and MMI270 reduced the number of myofibroblasts at day 28 without changing differentiation, proliferation or apoptosis of myofibroblasts or fibroblasts. Next, myofibroblasts in allograft airway fibrosis were demonstrated to be almost exclusively of extrapulmonary origin by analyzing RT1An positive myofibroblasts in an animal model combining orthotopic lung transplantation (from Lewis (RT1Al) to F1 (Brown,Norway (RT1An) × Lewis)) and intrapulmonary tracheal transplantation (from a Wister,Furth rat (RT1Au) into the transplanted Lewis-derived lung). Using peripheral blood mononuclear cells (PBMCs) that can differentiate into ,-SMA positive myofibroblasts in vitro, we demonstrated their contribution to the myofibroblast population of allograft airway fibrosis in vivo using a fluorescence-labeling cell tracking system. Moreover, PBMC-derived fibroblast-like cells expressed high levels of MMP-9 and MMP-12 and their migration was inhibited by MMP inhibitors in a wound healing assay. In conclusion, MMP-dependent migration of PBMC-derived myofibroblast precursors is an important contributing mechanism to the development of allograft airway fibrosis. [source]

Alcohol Primes the Airway for Increased Interleukin-13 Signaling

ALCOHOLISM, Issue 3 2009
Patrick O. Mitchell
Background:, Using an experimental model of airway fibrosis following lung transplantation, we recently showed that chronic alcohol ingestion by donor rats amplifies airway fibrosis in the recipient. Associated with alcohol-mediated amplification of airway fibrosis is increased transforming growth factor ,-1(TGF,1) and ,-smooth muscle actin expression. Other studies have shown that interleukin-13 (IL-13) modulates TGF,1 signaling during experimentally-induced airway fibrosis. Therefore, we hypothesized that IL-13 is a component of alcohol-mediated amplification of pro-fibrotic mediators in the alcoholic lung. Methods:, To test this hypothesis, we analyzed tracheal epithelial cells and type II alveolar cells from control- or alcohol-fed rats, alcohol-treated mouse lung fibroblasts, and human bronchial epithelial cells in vitro for expression of various components of the IL-13 signaling pathway. Signaling via the IL-13 pathway was assessed by measuring levels of phosphorylated signal transducers and activators of transcription-6 (STAT6). In addition, we performed heterotopic tracheal transplantation using control-fed and alcohol-fed donor rats and analyzed tracheal allografts for expression of components of the IL-13 signaling pathway by RT-PCR and immunocytochemical analyses. Results:, Interleukin-13 expression was detected in type II alveolar epithelial cells and human bronchial epithelial cells, but not in lung fibroblasts. IL-13 expression was decreased in whole lung and type II cells in response to alcohol exposure. In all cell types analyzed, expression of IL-13 signaling receptor (IL-13R,1) mRNA was markedly increased. In contrast, mRNA and protein expression of the IL-13 decoy receptor (IL-13R,2) were decreased in all cells analyzed. Exposure to alcohol also increased STAT6 phosphorylation in response to IL-13 and lipopolysaccharide. Conclusions:, Data from multiple cell types in the pulmonary system suggest that IL-13 and its receptors play a role in alcohol-mediated activation of pro-fibrotic pathways. Taken together, these data suggest that alcohol primes the airway for increased IL-13 signaling and subsequent tissue remodeling upon injury such as transplantation. [source]

Translational Research: Animal Models of Obliterative Bronchiolitis after Lung Transplantation

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2009
M. Sato
Obliterative bronchiolitis (OB) or chronic graft dysfunction remains the major limitation to long-term success of lung transplantation. Investigation using animal models is a critical component of research to understand the underlying pathological mechanisms and to develop novel preventive and therapeutic strategies for OB. Multiple animal models of OB exist, including orthotopic lung transplantation in rodents and large animals, orthotopic tracheal transplantation and heterotopic transplantation of a trachea in variable sites such as subcutaneous, intraomental and intrapulmonary sites. The most important issue for researchers is not specifically which model is the best but which is the most appropriate model to test their scientific hypothesis. For example, while orthotopic lung transplantation best mimics the overall surgical procedure, a question regarding fibrotic processes of OB may be better answered using heterotopic tracheal transplant models because of their reliable reproducibility of allograft obliterative airway fibrosis. Animal models should be continuously refined, modified and sometimes combined to fit the particular research purpose. We review the available animal models, their modifications and possible applications to assist researchers in choosing the appropriate model for their intended research. [source]