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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Public Health & Prev Medicine
Schools of Public Health
United States
Zip Code
Haak, Andrew J; Girtman, Megan A; Ali, Mohamed F et al. (2017) Phenylpyrrolidine structural mimics of pirfenidone lacking antifibrotic activity: A new tool for mechanism of action studies. Eur J Pharmacol 811:87-92
Haak, Andrew J; Tan, Qi; Tschumperlin, Daniel J (2017) Matrix biomechanics and dynamics in pulmonary fibrosis. Matrix Biol :
Tjin, Gavin; White, Eric S; Faiz, Alen et al. (2017) Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis. Dis Model Mech 10:1301-1312
Schafer, Marissa J; White, Thomas A; Iijima, Koji et al. (2017) Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 8:14532
Sicard, Delphine; Fredenburgh, Laura E; Tschumperlin, Daniel J (2017) Measured pulmonary arterial tissue stiffness is highly sensitive to AFM indenter dimensions. J Mech Behav Biomed Mater 74:118-127
Dieffenbach, Paul B; Haeger, Christina Mallarino; Coronata, Anna Maria F et al. (2017) Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2. Am J Physiol Lung Cell Mol Physiol 313:L628-L647
Tan, Qi; Choi, Kyoung Moo; Sicard, Delphine et al. (2017) Human airway organoid engineering as a step toward lung regeneration and disease modeling. Biomaterials 113:118-132
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

Showing the most recent 10 out of 22 publications