Pulmonary fibrosis is a pathological response to a diverse group of recognized and unrecognized insults. Both histologic studies from patients with pulmonary fibrosis and animal studies of fibrotic lung disease have demonstrated that the inability to re-establish a normal epithelium is predictive of progression to fibrosis, while normal healing of epithelial cells predicts recovery without fibrosis. We postulate that alveolar epithelial cells (AEC) participate in reciprocal, local regulatory interactions with pulmonary macrophages to defend the integrity of the alveolar epithelial layer. Our preliminary data demonstrate that impaired AEC production of granulocyte-macrophage colony stimulating factor (GM-CSF) plays a crucial role in dysfunctional epithelial cell regeneration and the development of fibrosis. The central hypothesis of this application is that AEC and macrophages participate in a bi-directional paracrine interaction, in which AEC-derived GM-CSF leads to the expression of macrophage mediators, such as hepatocyte growth factor (HGF), that preserve normal alveolar architecture. When AEC expression of GM-CSF is impaired in the setting of inflammation, the alveolar microenvironment is altered so that HGF and fibrinolytic activity are diminished, with pulmonary fibrosis as the consequence, rather than normal repair. These hypotheses will be tested in a bleomycin-induced rat model of pulmonary fibrosis. Based on this hypothesis, we have designed studies to accomplish 5 goals: 1) To compare the regulation and production of GM-CSF in AEC from normal and bleomycin- injured rats in vitro. We will define the time course of impaired GM-CSF expression and compare GM-CSF expression in response to inflammatory agonists in type II cells from bleomycin-treated animals to controls. 2) To determine the molecular mechanisms of diminished GM-CSF expression by type II cells from bleomycin treated animals. Experiments will determine whether impaired GM-CSF mRNA expression after bleomycin exposure is a consequence of altered GM-CSF transcription and/or mRNA stability. 3) To define the role of GM-CSF in the regulation of activity of macrophages isolated from the lungs of normal and bleomycin-treated animals. Experiments will be performed to test the hypothesis that GM-CSF, alone or in conjunction with other cytokines, produces and maintains alveolar and/or interstitial macrophages that express HGF, IL-1beta, and uPA, a series of products beneficial to lung repair. 4) To determine the influence of HGF on type II AEC from both normal and bleomycin-treated animals. Experiments will be performed to examine the ability of HGF to influence type II cell proliferation and uPA expression during the time course of response to bleomycin. 5) To determine the pathogenetic role and therapeutic benefit of networks involving GM-CSF in the fibrotic response. The effects of modulation of GM-CSF activity in vivo on the fibrotic response will be determined using neutralizing antibodies to block and gene transfer to enhance AEC expression of GM-CSF. Understanding epithelial cell-macrophage interactions will provide the necessary insights into fibrotic and non-fibrotic repair required for novel therapies directed at epithelial cells or pulmonary macrophages.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Ann Arbor
United States
Zip Code
Schmidt, S L; Nambiar, A M; Tayob, N et al. (2011) Pulmonary function measures predict mortality differently in IPF versus combined pulmonary fibrosis and emphysema. Eur Respir J 38:176-83
Trujillo, Glenda; Meneghin, Alessia; Flaherty, Kevin R et al. (2010) TLR9 differentiates rapidly from slowly progressing forms of idiopathic pulmonary fibrosis. Sci Transl Med 2:57ra82
Fell, Charlene D; Martinez, Fernando J; Liu, Lyrica X et al. (2010) Clinical predictors of a diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 181:832-7
Huang, Steven K; White, Eric S; Wettlaufer, Scott H et al. (2009) Prostaglandin E(2) induces fibroblast apoptosis by modulating multiple survival pathways. FASEB J 23:4317-26
Fell, Charlene D; Liu, Lyrica Xiaohong; Motika, Caroline et al. (2009) The prognostic value of cardiopulmonary exercise testing in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 179:402-7
White, Kimberly E; Ding, Qiang; Moore, Bethany B et al. (2008) Prostaglandin E2 mediates IL-1beta-related fibroblast mitogenic effects in acute lung injury through differential utilization of prostanoid receptors. J Immunol 180:637-46
Huang, Steven K; Peters-Golden, Marc (2008) Eicosanoid lipid mediators in fibrotic lung diseases: ready for prime time? Chest 133:1442-50
Han, M K; Murray, S; Fell, C D et al. (2008) Sex differences in physiological progression of idiopathic pulmonary fibrosis. Eur Respir J 31:1183-8
Muro, Andres F; Moretti, Federico A; Moore, Bethany B et al. (2008) An essential role for fibronectin extra type III domain A in pulmonary fibrosis. Am J Respir Crit Care Med 177:638-45
Huang, Steven K; Wettlaufer, Scott H; Hogaboam, Cory M et al. (2008) Variable prostaglandin E2 resistance in fibroblasts from patients with usual interstitial pneumonia. Am J Respir Crit Care Med 177:66-74

Showing the most recent 10 out of 96 publications