Pulmonary fibrosis may result from dysregulated wound healing responses to sequential lung injuries. Recruitment of circulating bone-marrow-derived mesenchymal precursors (fibrocytes) is crucial for a fibroproliferative host response post-injury. Fibrocytes contribute to extracellular matrix (ECM) generation and promote fibrosis through the secretion of profibrotic/proinflammatory factors. A focal alveolar epithelial cell (AEC) injury is believed to be the initiating event of the fibrotic process. The etiologic agents of lung injury are unknown but latent viral infections, especially by members of the herpesvirinae have been associated with idiopathic pulmonary fibrosis (IPF). Viral infection might influence fibroproliferative responses via lysis of parenchymal lung cells or by inducing alterations in the function(s) of resident or recruited cells. Infection of mice with MHV-68 (a murine gammaherpesvirus) results in both lytic and latent infection of AECs and mimics human infection with Epstein-Barr virus (EBV). Our preliminary data demonstrate 1) MHV-68 infection augments fluorescein isothiocyanate (FITC)-induced lung fibrosis when given both prior to or after the fibrotic insult. 2) Fibrocytes are recruited to the lung in response to MHV-68 infection. 3) MHV-68 infection results in the generation of cysteinyl leukotrienes (cys LTs) which can induce migration and activation of fibrocytes. 4) MHV-68 can infect fibrocytes and enhance their proliferation. 5) The additional alveolar injury induced by FITC, induces a dysregulated cytokine and eicosanoid response which favors fibrocyte proliferation, differentiation and ECM deposition. We hypothesize that increased fibrosis following MHV-68 infection/FITC injury is the result of enhanced recruitment, proliferation and differentiation of fibrocytes. Recruitment and proliferation are increased due to releases of cys LTs and CC chemokines by resident cells of the lung. Differentiation is enhanced by production of altered ratios of fibrocyte stimulatory and protective molecules by parenchymal and recruited cells. Completion of the following specific aims will provide new information regarding mechanisms that lead to generation of or exacerbation of pulmonary fibrosis.
Aim 1) To determine the kinetics and role of alveolar MHV-68 infection in augmentation of FITC-induced pulmonary fibrosis;
Aim 2) To determine whether MHV-68 infection alters the secretion of pro- or anti-fibrotic mediators by AECs, alveolar macrophages (AMs), interstitial macrophages (IMs) and B cells and to perform correlative studies in human AMs infected with EBV;
Aim 3) To determine whether MHV-68 infection recruits more fibrocytes to the lung, whether MHV-68 or EBV infection alters fibrocytes and fibroblasts and to determine the role of cys LTs in MHV-68-induced recruitment of fibrocytes and augmentation of fibrosis. Project Narrative/Relevance The experiments proposed in this application will provide mechanistic insight into the role that viral infections may play in predisposing people to the development of fibrosis. Research will also address the role that viral infections play in exacerbating disease in patients with established fibrosis. Finally, this work will explore the therapeutic potential of anti-leukotriene strategies to limit viral-induced exacerbations of fibrosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-RES-B (02))
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Reynolds, Herbert Y
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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