Progressive fibrosis is a hallmark of interstitial lung diseases such as idiopathic pulmonary fibrosis. Fibrosis stiffens the lung parenchyma. Preliminary data provided in this proposal demonstrate that normal lung parenchymal tissue is more compliant than previously predicted, and that highly localized increases in the stiffness of fibrotic lesions are much greater than previously recognized. Fibroblasts grown on substrates as stiff as fibrotic lesions engage in rapid proliferation and abundant matrix synthesis;in marked contrast these behaviors are largely suppressed on substrates as compliant as normal lung tissue. The central hypothesis that we pose based on these data is that the mechanical environment present in lung fibrosis triggers a "fibrogenesis program" in resident fibroblasts that promotes feedback amplification of the disease. We propose four specific aims: (1) quantify the stiffness of the parenchyma in normal lung tissue and developing and established fibrotic lesions;(2) test whether the transition in matrix stiffness from normal to fibrotic levels is a necessary precondition for lung fibroblast proliferation and fibrogenic activation;(3) test the role played by cytoskeletal dynamics and serum response factor activation in driving stiffness-dependent fibroblast biology;and (4) identify key transcription factors coordinating fibroblast transitions between quiescent and fibrogenic states when transferred between compliant and stiff matrices.
These aims will be carried out in novel 2D and 3D models that allow clear delineation of the effects of lung matrix stiffness on key fibrogenic behaviors of lung fibroblasts. Throughout the experimental plan we will examine the interplay between matrix stiffness and the soluble environment present in fibrosis as it impacts on fibroblast biology. This research will generate novel insights into the molecular mechanisms of stiffness-dependent fibroblast activation in fibrotic lungs, and identify critical regulators of fibrogenesis suitable for therapeutic targeting.

Public Health Relevance

Lung fibrosis stiffens affected tissue. The experiments proposed here will test whether pathophysiological changes in stiffness promote fibrosis by stimulating lung fibroblasts. Understanding the role mechanical factors play in fibroblast activation could lead to new strategies to treat fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092961-04
Application #
8307788
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
2009-08-06
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$408,992
Indirect Cost
$125,730
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Liu, Fei; Haeger, Christina Mallarino; Dieffenbach, Paul B et al. (2016) Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension. JCI Insight 1:
Tschumperlin, Daniel J (2015) Matrix, mesenchyme, and mechanotransduction. Ann Am Thorac Soc 12 Suppl 1:S24-9
Liu, Fei; Lagares, David; Choi, Kyoung Moo et al. (2015) Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Physiol Lung Cell Mol Physiol 308:L344-57
Shkumatov, Artem; Thompson, Michael; Choi, Kyoung M et al. (2015) Matrix stiffness-modulated proliferation and secretory function of the airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 308:L1125-35
Prakash, Y S; Tschumperlin, Daniel J; Stenmark, Kurt R (2015) Coming to terms with tissue engineering and regenerative medicine in the lung. Am J Physiol Lung Cell Mol Physiol 309:L625-38
Tschumperlin, Daniel J (2013) Fibroblasts and the ground they walk on. Physiology (Bethesda) 28:380-90
Tschumperlin, Daniel J; Liu, Fei; Tager, Andrew M (2013) Biomechanical regulation of mesenchymal cell function. Curr Opin Rheumatol 25:92-100
Marinković, Aleksandar; Liu, Fei; Tschumperlin, Daniel J (2013) Matrices of physiologic stiffness potently inactivate idiopathic pulmonary fibrosis fibroblasts. Am J Respir Cell Mol Biol 48:422-30
Mih, Justin D; Marinkovic, Aleksandar; Liu, Fei et al. (2012) Matrix stiffness reverses the effect of actomyosin tension on cell proliferation. J Cell Sci 125:5974-83
Marinkovic, Aleksandar; Mih, Justin D; Park, Jin-Ah et al. (2012) Improved throughput traction microscopy reveals pivotal role for matrix stiffness in fibroblast contractility and TGF-ýý responsiveness. Am J Physiol Lung Cell Mol Physiol 303:L169-80

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