Fibrotic cytokine phenotypes, interstitial lung disease

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

(Applicant's Abstract) The initiation and maintenance of chronic interstitial pulmonary inflammation, leading to fibrosis, is often due to dynamic interactions between an inciting agent, inflammatory mediators, leukocytes, and structural cells of the lung. Independent of the various etiologies, many fibrotic interstitial lung diseases appear to possess a number of similar pathologic responses, including an initial elicitation of various leukocyte populations to the lung, subsequent fibroblast activation and proliferation, and deposition of extracellular matrix. Understanding the cellular and molecular mechanisms which are responsible for fibroblast activation during the initiation, maintenance, and resolution of interstitial luna inflammation are the broad, long-term objectives of this application. The working hypothesis of this proposal is the following: an exacerbation of fibroblast activation and tissue fibrosis during the evolution of chronic, interstitial lung inflammation is dependent upon the expression of a specific disease phenotype characterized by type 2 cytokines. These fibroblasts mechanistically contribute to the evolution of lung pathology by synthesizing subsequent pro-fibrotic mediators, which result in the perpetuation of lung fibrosis. This hypothesis will be addressed by focusing on fibrotic mechanisms which occur during the development of a Th1 (minimally fibrotic) versus a Th2 type (fibrotic) immune response in the lung. Specific areas of cytokine biology that will be assessed include: 1) the contribution of the interleukin- 4/interleukin-13 axis, to fibroblast activation; 2) the role of Thl-like cytokines in altering fibroblast activation; 3) a proteomic and genomic assessment of fibroblasts isolated from type 1 or type 2 lesions; and 4) the contribution of eosinophils and lymphocytes, isolated from animals with ongoing Th2 responses, or lymphocytes recovered from animals with type1 responses, to influence fibroblast activation in vitro. Animal models of chronic interstitial lung inflammation will be utilized to assess the contribution of Th1 like and Th2 like cytokines during pulmonary fibroblast activation and lung collagen deposition. A number of techniques will be employed in this application including: the use of novel tissue arrays, microarrays, and laser capture microscopy; quantitative reverse transcription-polymerase chain reaction (RT-P('-R)-TaqMan; mRNA stability; and the use of immunohistochermistry for antigen localization and ELISAs for the quantitation of cytokines.