This proposal is a competitive renewal application for HL-45136. Previous work showed that lung injury activates a local tissue angiotensin system in pulmonary alveolar epithelial cells (AECs) and demonstrated that de novo synthesis of angiotensin (ANG) II is required for AEC apoptosis and subsequent lung fibrosis in animal models. An important component of this system that has not been studied well is angiotensin converting enzyme-2 (ACE-2), a carboxypeptidase that degrades ANGII to form ANG1-7, a heptapeptide that blocks ANGII action. Exciting new Preliminary Data show that ACE-2 protein and mRNA are severely downregulated in both human Idiopathic Pulmonary Fibrosis and in animal models of this disease induced by bleomycin. In vivo and cell culture studies suggest that ACE-2 protects against lung fibrosis and AEC apoptosis by limiting the local accumulation of ANGII and by producing ANG1-7, which downregulates the ANGII receptor AT1. However, the roles and mechanisms of action of ACE-2 and its product ANG1-7 in AECs are unknown. This proposal is designed to begin elucidating the function(s) of ACE-2 and ANG1-7 in AEC survival in the context of lung fibrogenesis, and to begin defining the mechanisms by which ACE-2 is downregulated in experimental lung fibrosis.
Aim1 will determine if cell type-selective knockdown or overexpression of ACE-2 specifically in AECs is sufficient to enhance or inhibit, respectively, bleomycin-induced AEC apoptosis and lung fibrosis in mice.
Aim2 will define the molecular mechanisms responsible for downregulation of AEC-2 mRNA by profibrotic stimuli in cultured AECs and in a mouse model of lung fibrosis.
In Aim 3, the roles of ACE-2 and ANG1-7 in AEC survival will be elucidated in studies of cultured AECs.
Aim4 will begin defining the molecular mechanisms by which ANG1-7, acting through its receptor mas,inhibits the effects of ANGII on AECs. Together, these studies will increase our understanding of a critical component of the local angiotensin system in the lungs and may provide new information useful in the future design of novel therapeutics for Idiopathic Pulmonary Fibrosis.

Public Health Relevance

Previous work showed that lung injury activates a local tissue angiotensin system in pulmonary alveolar epithelial cells (AECs) and demonstrated that de novo synthesis of angiotensin (ANG) II is required for AEC apoptosis and subsequent lung fibrosis in animal models. An important component of this system that has not been studied well is angiotensin converting enzyme-2 (ACE-2), a carboxypeptidase that degrades ANGII to form ANG1-7, a heptapeptide that blocks ANGII action. This proposal is designed to begin elucidating the function(s) of ACE-2 and ANG1-7 in AEC survival in the context of lung fibrogenesis, and to begin defining the mechanisms by which ACE-2 is downregulated in experimental lung fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045136-23
Application #
8318261
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
1990-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
23
Fiscal Year
2012
Total Cost
$295,066
Indirect Cost
$97,066
Name
Michigan State University
Department
Physiology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Abdelwahab, Abdellatif; Gopallawa, Indiwari; Piasecki, Christopher C et al. (2016) Bleomycin-Induced Neonatal Lung Injury Requires the Autocrine Pulmonary Angiotensin System. Jacobs J Pulmonol 2:
Gopallawa, Indiwari; Uhal, Bruce D (2016) Angiotensin-(1-7)/mas inhibits apoptosis in alveolar epithelial cells through upregulation of MAP kinase phosphatase-2. Am J Physiol Lung Cell Mol Physiol 310:L240-8
Mohamed, Tarek L; Nguyen, Hang T; Abdul-Hafez, Amal et al. (2016) Prior hypoxia prevents downregulation of ACE-2 by hyperoxia in fetal human lung fibroblasts. Exp Lung Res 42:121-30
Oarhe, Chinyere I; Dang, Vinh; Dang, MyTrang et al. (2015) Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts. Pediatr Res 77:656-62
Gopallawa, Indiwari; Uhal, Bruce D (2014) Molecular and cellular mechanisms of the inhibitory effects of ACE-2/ANG1-7/Mas axis on lung injury. Curr Top Pharmacol 18:71-80
Uhal, Bruce D; Nguyen, Hang; Dang, MyTrang et al. (2013) Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1-7. Am J Physiol Lung Cell Mol Physiol 305:L33-41
Dang, My-Trang T; Gu, Chenyang; Klavanian, Jeannie I et al. (2013) Angiotensinogen promoter polymorphisms predict low diffusing capacity in U.S. and Spanish IPF cohorts. Lung 191:353-60
Uhal, Bruce D; Dang, MyTrang; Dang, Vinh et al. (2013) Cell cycle dependence of ACE-2 explains downregulation in idiopathic pulmonary fibrosis. Eur Respir J 42:198-210
Uhal, Bruce D; Nguyen, Hang (2013) The Witschi Hypothesis revisited after 35 years: genetic proof from SP-C BRICHOS domain mutations. Am J Physiol Lung Cell Mol Physiol 305:L906-11
Uhal, Bruce D; Li, Xiaopeng; Piasecki, Christopher C et al. (2012) Angiotensin signalling in pulmonary fibrosis. Int J Biochem Cell Biol 44:465-8

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