Idiopathic Pulmonary Fibrosis (IPF) is a progressive, fatal fibrotic lung disease for which there is no effective therapy. The sentinel morphological lesion is the fibroblastic focus, which is composed of myofibroblasts in a type I collagen rich matrix. Prima facie evidence supports the critical role for myofibroblasts in the relentless progression of IPF given that this is the cell that proliferates and deposits collagen in the alveolar wall. Although studies strongly support the notion that IPFfibroblasts display a distinct pathological phenotype, large gaps in knowledge remain regarding differences between the pathological nature of IPF fibroblasts responsible for progressive fibrosis and the physiologic function of myofibroblasts essential for normal lung repair. The objective of this proposal is to characterize the molecular processes underlying the pathological nature of IPF fibroblasts. Seminal studies have demonstrated that polymerized type I collagen acts as a negative regulator of fibroblast proliferation. Consistent with this, we have found that normal lung fibroblast proliferation is inhibited by polymerized collagen. In contrast, we have found that IPF fibroblasts have escaped this restraint. Our mechanistic studies of this phenomenon point to abnormalities in 01 integrin signaling in response to ligation with type I collagen. We have discovered that integrin-ECM interaction regulates PTEN expression and activity. PTEN is a phosphatase whose baseline activity is constitutively high. It functions by negatively regulating proliferation by repressing the integrin- PI3K/Akt signaling pathway. When normal lung fibroblasts are cultured on polymerized collagen, PTEN activity remains high. In contrast, when IPF fibroblasts are cultured on polymerized collagen PTEN activity is inappropriately low leaving the PI3K/Akt signaling pathway unrestrained. We hypothesize that in IPFfibroblasts 01 integrin-type I collagen interaction results in aberrant regulation of PTEN. To test our hypothesis we will:
Aim 1. Determine the role of the PI3K/Akt/S6K1-PTEN signaling axis in enabling IPF fibroblasts to elude the negative proliferative effects of polymerized type I collagen.
Aim 2. Define the molecular basis for regulation of PTEN and the PI3K/Akt signal pathway in control and IPF lung fibroblasts by 01 integrin-type I collagen interaction.
Aim 3. Validation of in vitro studies implicating abnormal function of the 01 integrin PI3K/Akt/S6K1-PTEN signaling axis in IPF fibrogenesis by in vivo methodology.

Public Health Relevance

The myofibroblast is the effector cell of the relentless IPF fibrotic response. We have discovered that IPF fibroblasts have exaggerated proliferation on polymerized collagen. The mechanism involves low PTEN activity that facilitates aberrant activation of the PI3K/Akt signal. These studies will delineate the molecular processes underlying the pathologically low PTEN activity in IPF fibroblasts and suggest new therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
United States
Zip Code
Liu, Tianju; Yu, Hongfeng; Ullenbruch, Matthew et al. (2014) The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis. PLoS One 9:e88362
Bodempudi, Vidya; Hergert, Polla; Smith, Karen et al. (2014) miR-210 promotes IPF fibroblast proliferation in response to hypoxia. Am J Physiol Lung Cell Mol Physiol 307:L283-94
Parker, Matthew W; Rossi, Daniel; Peterson, Mark et al. (2014) Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J Clin Invest 124:1622-35
Xia, Hong; Bodempudi, Vidya; Benyumov, Alexey et al. (2014) Identification of a cell-of-origin for fibroblasts comprising the fibrotic reticulum in idiopathic pulmonary fibrosis. Am J Pathol 184:1369-83
Liu, Tianju; Ullenbruch, Matthew; Young Choi, Yoon et al. (2013) Telomerase and telomere length in pulmonary fibrosis. Am J Respir Cell Mol Biol 49:260-8
Nho, Richard Seonghun; Peterson, Mark; Hergert, Polla et al. (2013) FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas. PLoS One 8:e61017
Nakashima, Taku; Liu, Tianju; Yu, Hongfeng et al. (2013) Lung bone marrow-derived hematopoietic progenitor cells enhance pulmonary fibrosis. Am J Respir Crit Care Med 188:976-84
Hu, Biao; Wu, Zhe; Hergert, Polla et al. (2013) Regulation of myofibroblast differentiation by poly(ADP-ribose) polymerase 1. Am J Pathol 182:71-83
Hu, Biao; Phan, Sem H (2013) Myofibroblasts. Curr Opin Rheumatol 25:71-7
Hu, Biao; Wu, Zhe; Nakashima, Taku et al. (2012) Mesenchymal-specific deletion of C/EBPýý suppresses pulmonary fibrosis. Am J Pathol 180:2257-67

Showing the most recent 10 out of 17 publications