The work, as detailed in this proposal, has focused on the mechanism(s) of protection that Suppressor of Cytokine Signaling - 1 (SOCS-1) confers in the setting of hyperoxic acute lung injury (HALI). Our preliminary data demonstrated that adenoviral treated mice that overexpress the suppressor of cytokine signaling-1(Ad-SOCS-1) are remarkably resistant to hyperoxic acute lung injury (HALI) and live significantly longer in hyperoxia when compared to green fluorescent protein tagged adeno virus (Ad-GFP) treated mice. SOCS-1 overexpressing mice are protected from hyperoxia-induced inflammation, which is associated with inactivation of purinergic P2X7 receptor (P2X7R)-mediated inflammasome, thus demonstrating a critical role for SOCS-1 in inflammasome-mediated inflammation. Either inflammasome silencing or SOCS-1 overexpression in monocytic cell line (THP-1) and co-cultured with alveolar type II (ATII) monolayer abolishes hyperoxia induced transepithelial permeability across mouse ATII cell monolayers and abrogates hyperoxia-induced secretion of pro-inflammatory cytokines. SOCS-1 overexpressing mice are protected from hyperoxia-induced inflammation and apoptosis, which is associated with apoptosis signal-regulating kinase 1 (ASK-1) inhibition. SOCS-1- induced protection against oxidant-induced death-inducing signaling complex (DISC) mediated apoptosis is associated with ASK-1 ubiquitination and degradation. These studies lead us to hypothesize that SOCS-1 confers protection against HALI by inhibiting inflammasome-mediated inflammation and DISC-induced apoptosis via ASK-1 degradation. We propose the following specific aims to investigate our hypothesis:
Aim 1 : To identify the role of ASK-1 in SOCS-1-induced protection against hyperoxia-induced DISC and inflammasome formation.
Aim 2 : To determine whether activation of ASK-1 has a role in hyperoxia-induced P2X7R mediated inflammasome formation.
Aim 3 : To identify the role of inflammasome in SOCS-1-induced protection against hyperoxia-induced inflammation and epithelial permeability. The proposed studies will elucidate the mechanisms by which SOCS-1 protects against HALI and will identify the cellular processes and genes critical for protection of the lung. The proposed studies will elucidate the precise role of SOCS-1 mediated inflammasome in acute lung injury (ALI) could also lead to the discovery of a totally novel therapeutic class of drugs that suppresses inflammation in ALI.

Public Health Relevance

Hyperoxia is a necessary part of treatment for patients with cardiovascular and pulmonary diseases. However, prolonged exposure to hyperoxia leads to acute lung injury (ALI). ALI is a major clinical problem in the United States with an estimated incidence rate of 262,500 patients and 40-50% mortality. Our preliminary data suggest that SOCS-1 protects against hyperoxia-induced inflammation and apoptosis. These protective effects of SOCS-1 in the setting of oxidative injury are associated with inflammasome inactivation. In this proposal we will study the role of inflammasome in acute lung injury. Our work may uncover new disease mechanisms and therapeutic approaches for lung injury associated syndromes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105932-02
Application #
8213420
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2011-02-01
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$367,500
Indirect Cost
$117,500
Name
University of South Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Saco, Tara V; Parthasarathy, Prasanna Tamarapu; Cho, Young et al. (2014) Role of epigenetics in pulmonary hypertension. Am J Physiol Cell Physiol 306:C1101-5
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Bandyopadhyay, Sayantani; Lane, Troy; Venugopal, Rajanbabu et al. (2013) MicroRNA-133a-1 regulates inflammasome activation through uncoupling protein-2. Biochem Biophys Res Commun 439:407-12

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