Approximately 150,000 people in the United States develop acute lung injury (All) and the acute respiratory distress syndrome (ARDS) annually (1). Despite research driven advances in therapy, ~40% of these patients will die. All and ARDS often manifest as a part of a systemic inflammatory process resulting in the development of diffuse alveolar epithelial damage and capillary injury with the exudation of protein rich fluid into the alveolar space. As part of the alveolar-capillary repair ALI/ARDS patients develop a fibroproliferative process that is characterized by the proliferation of mesenchymal cells, differentiation of mesenchymal cells into myofibroblasts and deposition of extracellular matrix. The molecular and cellular mechanisms underlying fibroproliferation during ALI and ARDS are not fully understood. Transforming growth factor-beta 1 (TGF-31) is integral for fibroblast activation and tissue repair. Multiple reports over the last 10 years have described a role for early fibroblast activation in determining the outcome of patients with the ARDS. How TGF-31 induces lung fibrosis following epithelial injury is not fully understood. To date there is no genetic evidence to indicate whether epithelial apoptosis is sufficient and required for the initiation of lung injury followed by pulmonary fibrosis. We propose that TGF-31 induces lung injury and fibrosis by activating the intrinsic apoptotic pathway in alveolar epithelial cells. The intrinsic apoptotic pathway is regulated by the Bcl-2 family members. In support of our hypothesis, we have reported that loss of the proapoptotic Bcl-2 family member Bid prevents TGF-31 induced fibrosis in mice. The purpose of this grant is to elucidate the mechanisms by which TGF-31 induces Bid dependent epithelial cell death resulting in lung injury and fibrosis. The current proposal will address these questions utilizing genetics in mouse models of lung injury and fibrosis.

Public Health Relevance

From a clinical perspective, mortality in ARDS is unacceptably high despite improved supportive care and ventilatory strategies. In vitro, animal and human data implicate TGF-31 action on alveolar epithelial cells as of primary importance in alveolar injury and repair. Our study has the potential to determine the role of TGF- 31 signaling pathway in epithelial apoptosis that may provide the rationale for the development of novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL071643-09
Application #
8376675
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$354,540
Indirect Cost
$122,055
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Wiese, Kristin M; Coates, Bria M; Ridge, Karen M (2017) The Role of Nucleotide-Binding Oligomerization Domain-Like Receptors in Pulmonary Infection. Am J Respir Cell Mol Biol 57:151-161
Lehmann, Clara; Berner, Reinhard; Bogner, Johannes R et al. (2017) The ""Choosing Wisely"" initiative in infectious diseases. Infection 45:263-268
Misharin, Alexander V; Morales-Nebreda, Luisa; Reyfman, Paul A et al. (2017) Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med 214:2387-2404
Gonzalez-Gonzalez, Francisco J; Chandel, Navdeep S; Jain, Manu et al. (2017) Reactive oxygen species as signaling molecules in the development of lung fibrosis. Transl Res 190:61-68
Nin, Nicolas; Muriel, Alfonso; Peñuelas, Oscar et al. (2017) Severe hypercapnia and outcome of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome. Intensive Care Med 43:200-208
Vadász, István; Sznajder, Jacob I (2017) Gas Exchange Disturbances Regulate Alveolar Fluid Clearance during Acute Lung Injury. Front Immunol 8:757
Wolff, Bernard J; Bramley, Anna M; Thurman, Kathleen A et al. (2017) Improved Detection of Respiratory Pathogens by Use of High-Quality Sputum with TaqMan Array Card Technology. J Clin Microbiol 55:110-121
Magnani, Natalia D; Dada, Laura A; Queisser, Markus A et al. (2017) HIF and HOIL-1L-mediated PKC? degradation stabilizes plasma membrane Na,K-ATPase to protect against hypoxia-induced lung injury. Proc Natl Acad Sci U S A 114:E10178-E10186
McElroy, G S; Chandel, N S (2017) Mitochondria control acute and chronic responses to hypoxia. Exp Cell Res 356:217-222
Zheng, Zhikun; Chiu, Stephen; Akbarpour, Mahzad et al. (2017) Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction. Sci Transl Med 9:

Showing the most recent 10 out of 176 publications