Acute respiratory distress syndrome (ARDS) is a critical illness that afflicts an estimated 200,000 patients/year in the United States alone, kills approximately 75,000, and is seriously debilitating for many survivors. Specific ARDS therapies do not currently exist, and efforts to reduce its burden have been limited by an incomplete characterization of the diverse molecular mechanisms underlying its pathogenesis. The cardinal, morbidity-producing feature of ARDS is non-cardiogenic pulmonary edema resulting from pulmonary vascular barrier disruption with consequent alveolar flooding, and respiratory failure. The conceptual underpinning for these events consists of cytoskeletal contraction of pulmonary endothelial cells (ECs) leading to the formation of paracellular gaps. Novel strategies which reduce the vascular permeability and lung edema of ARDS are desperately needed. The objective of this proposal is to determine the contribution of the tumor suppressor WWOX to the pathobiological processes associated with ARDS. WWOX resides at the second most active common chromosomal fragile site in the human genome, making it highly susceptible to genotoxic stress such as that which occurs during cigarette smoke and other toxic respiratory exposures. Data detailed in this application suggests that 1) loss of WWOX occurs in the lung during cigarette smoke exposure, and this event may at least partly explain an increased susceptibility for severe ARDS in smokers versus nonsmokers observed in currently emerging evidence from epidemiologic studies, and 2) WWOX exerts potent EC barrier-protective effects during both in vivo and in vitro lipopolysaccharide (LPS)-induced ARDS. This project aims to 1) determine the significance of EC WWOX expression in murine ARDS, 2) define the molecular mechanisms by which WWOX promotes EC barrier protection and 3)Establish the conceptual basis for WWOX-based therapy in cigarette-smoke primed, sepsis-induced ARDS.

Public Health Relevance

/Relevance Acute Respiratory Distress Syndrome (ARDS) is a critical illness that afflicts an estimated 200,000 patients/year in the United States alone, kills approximately 75,000, and seriously debilitates many of its survivors. Specific ARDS therapies do not exist, and efforts to reduce ARDS burden have been limited by an incomplete characterization of the diverse molecular mechanisms underlying its pathogenesis. The proposed project seeks to address the current deficit in knowledge with regards to this important public health problem.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL140222-03
Application #
9983155
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Reineck, Lora A
Project Start
2018-08-01
Project End
2023-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612