Alveolar destruction and pulmonary fibrosis are juxtaposed in COPD and pulmonary fibrosis. Surprisingly, the relationships between these responses and the mechanisms that destroy alveoli while simultaneously nducing fibrosis have not been defined. Transforming Growth Factor-betal (TGF-b1) is expressed in an exaggerated fashion in COPD and pulmonary fibrosis and TGF-b1 abnormalities have been implicated in the pathogenesis of emphysema and scarring. The mechanisms that TGF-b1 uses to induce these different outcomes and the genetic factors that control these divergent responses have not been investigated. We developed novel triple transgenic mice overexpressing bioactive TGF-b1 in the murine lung. In 57BL/6 mice this TGF-b1 caused epithelial cell apoptosis, pulmonary fibrosis and honeycombing. In contrast, in Balb/c mice TGF-b1 caused emphysema with minimal tissue fibrosis. Exaggerated apoptosis and matrix metalloproteinase-12 induction were seen in Balb/c animals and prominent stimulation of lysyl oxidase, arginase II and Cyr-61 were seen in C57BL/6 animals. This led to the following hypothesis: 1. TGF-b1 is a multifunctional cytokine that simultaneously induces tissue injury and fibrosis and generates emphysematous and/or fibrotic phenotypes. 2. The tissue effects of TGF-b1 depend, in part, on the balance of apoptosis, proteolysis and fibrosis. 3. The ability of TGF-b1 to induce these divergent phenotypes is determined by definable TGF-b1 effector function regulating genes. To address this hypothesis, we propose to:
AIM #1. Generate and characterize inducible, lung-targeted TGF-b1 overexpressing (OE) transgenic mice on C57BL/6 and Balb/c genetic backgrounds.
AIM #2. Characterize the mechanisms that contribute to the different phenotypes that are induced by TGF- b1 in C57BL/6 and Balb/c transgenic animals.
AIM #3. Characterize the roles of the arginase system in the generation of the TGF-b1-induced phenotypes in C57BL/6 and Balb/c transgenic mice.
AIM #4. Define the genes that determine whether TGF-b1 induceds a predominantly fibrotic versus emphysematous response in C57BL/6 and Balb/c mice.
|Kang, Min-Jong; Yoon, Chang Min; Nam, Milang et al. (2015) Role of Chitinase 3-Like-1 in Interleukin-18-Induced Pulmonary Type 1, Type 2, and Type 17 Inflammation; Alveolar Destruction; and Airway Fibrosis in the Murine Lung. Am J Respir Cell Mol Biol 53:863-71|
|Lee, Chang-Min; Park, Jin Wook; Cho, Won-Kyung et al. (2014) Modifiers of TGF-?1 effector function as novel therapeutic targets of pulmonary fibrosis. Korean J Intern Med 29:281-90|
|Kang, Min-Jong; Choi, Je-Min; Kim, Bo Hye et al. (2012) IL-18 induces emphysema and airway and vascular remodeling via IFN-?, IL-17A, and IL-13. Am J Respir Crit Care Med 185:1205-17|
|Lee, Chun Geun; Herzog, Erica L; Ahangari, Farida et al. (2012) Chitinase 1 is a biomarker for and therapeutic target in scleroderma-associated interstitial lung disease that augments TGF-?1 signaling. J Immunol 189:2635-44|
|Dela Cruz, Charles S; Kang, Min-Jong; Cho, Won-Kyung et al. (2011) Transgenic modelling of cytokine polarization in the lung. Immunology 132:9-17|
|Matsuura, Hiroshi; Hartl, Dominik; Kang, Min-Jong et al. (2011) Role of breast regression protein-39 in the pathogenesis of cigarette smoke-induced inflammation and emphysema. Am J Respir Cell Mol Biol 44:777-86|
|Choi, Je-Min; Shin, Jae-Hun; Sohn, Myung-Hyun et al. (2010) Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation. Proc Natl Acad Sci U S A 107:18575-80|
|Sohn, Myung Hyun; Kang, Min-Jong; Matsuura, Hiroshi et al. (2010) The chitinase-like proteins breast regression protein-39 and YKL-40 regulate hyperoxia-induced acute lung injury. Am J Respir Crit Care Med 182:918-28|
|Lee, Chun Geun; Hartl, Dominik; Lee, Gap Ryol et al. (2009) Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis. J Exp Med 206:1149-66|
|Hartl, Dominik; He, Chuan Hua; Koller, Babara et al. (2009) Acidic mammalian chitinase regulates epithelial cell apoptosis via a chitinolytic-independent mechanism. J Immunol 182:5098-106|
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