Basic-Translational Research
Patrick Belvitch, MD
Steven Dudek, MD
Dustin Fraidenburg, MD
Jeffrey Jacobson, MD

Irena Levitan, PhD
Viswanathan Natarajan, PhD
Gye Young Park, MD
Sunit Singla, MD

Clinical-Outcomes Research
Kevin Haas, MD
Min Joo, MD
Chris Kapp, MD

Kevin Kovitz, MD, MBA
Jerry A. Krishnan, MD, PhD
Marisol Munoz, MSN, FNP-BC
Mary Pasquinelli, DNP, FNP-BC
Bharati Prasad, MD

Israel Rubinstein, MD

Health Services Research
Andrea Pappalardo, MD

SUNIT SINGLA, MD LAB


Sunit Singla MD

Assistant Professor of Medicine

ARDS Pathobiology and Therapeutics

The long-term objective of our lab is to cultivate a program of research that contributes towards maintaining a pipeline of novel therapeutic strategies targeting inflammation and vascular leak during acute respiratory distress syndrome (ARDS).

Specifically, the approach taken by this research program is to (1) identify dysregulated genes in patients exposed to cigarette smoke and other environmental toxins that may biologically inform the means by which these environmental exposures increase the risk for ARDS, (2) determine the underlying molecular mechanism(s) linking environmental exposures to ARDS risk via identified candidate gene(s), and (3) develop novel candidate gene(s)-based therapeutic strategies that can be tested in available animal models and advanced towards clinical investigations.

Current efforts are focused on several areas along the translational research spectrum:
1) Characterizing novel subsets of patients at increased risk for ARDS
2) Determining the mechanistic contribution of WWOX gene downregulation in smoke/vapor-priming of vascular leak during ARDS
3) Executing a phase IIb clinical trial as part of a multicenter effort to examine the safety and efficacy of therapeutic hypothermia in ARDS

Selected Key Publications

Zeng Z, Chen W, Moshensky A, Shakir Z, Khan R, Crotty Alexander LE, Ware LB, Aldaz CM, Jacobson JR, Dudek SM, Natarajan V, Machado RF, Singla S. Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS. Am J Respir Cell Mol Biol. 2021 Jan;64(1):89-99. doi: 10.1165/rcmb.2020-0145OC. PMID: 33058734; PMCID: PMC7780991.

Singla, Sunit; Chen, Jiwang; Sethuraman, Shruthi; Sysol, Justin R.; Gampa, Amulya; Zhao, Shuangping; Machado, Roberto F. Loss of Lung WWOX Expression Causes Neutrophilic Inflammation. AJP: Lung Cellular and Molecular Physiology. 2017 Mar 10. Epub ahead of print. PMID: 28283473

Singla, Sunit; Sysol, Justin; Dille, Benjamin; Chen, Jiwang; Machado, Roberto F. Hemin Causes Lung Microvascular Endothelial Barrier Dysfunction by Necroptotic Cell Death. American Journal of Respiratory Cell and Molecular Biology. American Journal of Respiratory Cell and Molecular Biology. 2017 Apr 19. Epub ahead of print. PMID: 28421813

Singla, Sunit; Zhou, Tong; Javaid, Kamran; Zhang, Wei; Ma, Shwu-Fan; Wade, Michael S.; Noth, Imre; Sweiss, Nadera J.; Garcia, Joe G.N.; Machado, Roberto F. Expression Profiling Elucidates A Molecular Gene Signature Which Identifies Pulmonary Hypertension In Sarcoidosis. Pulmonary Circulation. 2016 Dec; 6(4): 465–471. PMCID: PMC5210052

Singla, Sunit; Predescu, Dan; Bardita, Cristina; Wang, Minhua; Zhang, Jian; Balk, Robert A.; Predescu, Sanda. Pro-inflammatory endothelial cell dysfunction is associated with intersectin-1s down-regulation. Respir Res.12; 2011 Apr 12:46.PMID:21486462

 

Research

Role of lung WWOX deficiency in vascular leak during lung injury
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. The major goals are to 1) determine the significance of endothelial cell WWOX expression in murine ARDS, 2) define the molecular mechanisms by which WWOX promotes endothelial barrier protection, and 3)establish the conceptual basis for WWOX-based therapy in cigarette-smoke primed, sepsis-induced ARDS.

Zeng Z, Chen W, Moshensky A, Shakir Z, Khan R, Crotty Alexander LE, Ware LB, Aldaz CM, Jacobson JR, Dudek SM, Natarajan V, Machado RF, Singla S. Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS. Am J Respir Cell Mol Biol. 2021 Jan;64(1):89-99. doi: 10.1165/rcmb.2020-0145OC. PMID: 33058734; PMCID: PMC7780991.

Singla, Sunit; Chen, Jiwang; Sethuraman, Shruthi; Sysol, Justin R.; Gampa, Amulya; Zhao, Shuangping; Machado, Roberto F. Loss of Lung WWOX Expression Causes Neutrophilic Inflammation. AJP: Lung Cellular and Molecular Physiology. 2017 Mar 10. Epub ahead of print. PMID: 28283473

Risk and Severity of Acute Respiratory Distress Syndrome Following Chronic E-cigarette Aerosols Exposure
The rise of e-cigarette use (vaping) in the United States has been dramatic over the past decade, especially in adolescent and young adult populations. The knowledge gap regarding the adverse health effects of e-cigarette vapor (EV) needs to be addressed urgently to protect public health from an emerging onslaught of potential toxicities associated with chronic exposure. Chronic cigarette smoke (CS) exposure is known to increase the risk and severity of acute respiratory distress syndrome (ARDS). ARDS is a critical illness that afflicts an estimated 200,000 patients/year in the United States alone, with a 46% mortality rate in severe cases. These numbers dramatically increase during respiratory viral pandemics such as the H1N1 influenza pandemic of 2009, and the current coronavirus-related global disaster. A biomarker for increased ARDS susceptibility following CS exposure is a decrease WWOX expression detectable in blood, airway cells, and lung tissue. Mice exposed chronically to e-cigarette aerosols have been found to exhibit decreased lung WWOX expression and an increased severity of ARDS following gram-negative endotoxin instillation in the airways. Activities in this project include 1) utilizing diverse clinically relevant challenges to identify increased ARDS susceptibility induced by e-cigarette aerosols, 2) characterizing variants in EV composition that may enhance priming for ARDS, and 3) identifying viable susceptibility biomarkers for aerosol-induced increases in ARDS risk. The overall goal is to improve scientific knowledge of the toxicity and health effects of e-cigarettes.

Zeng Z, Chen W, Moshensky A, Shakir Z, Khan R, Crotty Alexander LE, Ware LB, Aldaz CM, Jacobson JR, Dudek SM, Natarajan V, Machado RF, Singla S. Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS. Am J Respir Cell Mol Biol. 2021 Jan;64(1):89-99. doi: 10.1165/rcmb.2020-0145OC. PMID: 33058734; PMCID: PMC7780991.

Cooling to Help Injured Lungs (CHILL) Phase 2b Randomized Control Trial of Therapeutic Hypothermia in Patients with ARDS
We are part of a multicenter network performing this Phase IIb randomized clinical trial to study the potential benefit and safety of mild hypothermia in patients with ARDS using 28-day ventilator-free days and other clinical and laboratory surrogates for mortality. This study will generate the necessary information to determine whether and how to design a definitive Phase III clinical trial of therapeutic hypothermia to reduce mortality in patients with ARDS. This trial will compare mild hypothermia (34°-35°C) plus neuromuscular blockade vs. standard temperature management in patients with moderate to severe ARDS.

https://www.clinicaltrials.gov/ct2/show/NCT04545424?term=chill&cond=Ards&draw=2&rank=1

Lab Members

Weiguo Chen, MD/PhD
Research Assistant Professor

[email protected]

Malvika Kaul, MD
[email protected]

Hannah Carlson
Clinical Research Coordinator – CHILL Study

[email protected]

Former Trainees

Visiting Professor:
Zhenguo Zeng, MD/PhD August, 2018 – August, 2019

First Affiliated Hospital of Nanchang University, Jiangxi, China
Associate Professor of Medicine

Zeng, Zhenguo; Chen, Weiguo; Moshensky, Alexander; Shakir, Zaid; Khan, Raheel; Crotty-Alexander, Laura; Ware, Lorraine B.; Aldaz, Marcelo; Jacobson, Jeffrey R.; Dudek, Steven M.; Natarajan, Vishwanathan; Machado, Roberto F.; Singla, Sunit. Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS. Am J Respir Cell Mol Bio. 2021 Jan;64(1):89-99. PMID: 33058734

Singla, Sunit; Zeng, Zhenguo; Chen, Weiguo; Demeritte, Regaina; Chen, Jiwang; Jacobson, Jeffrey R.; Dudek, Steven M.; Natarajan, Vishwanathan; Machado, Roberto F. Endothelial-Specific Knockdown of Lung WWOX Expression Worsens Acute Lung Injury. Am J Respir Crit Care Med 2019; 199:A4398.

Fellows:
Benjamin Dille, MD 2016-17

Pediatric Critical Care Medicine, University of Illinois at Chicago

Singla, Sunit; Sysol, Justin; Dille, Benjamin; Chen, Jiwang; Machado, Roberto F. Hemin Causes Lung Microvascular Endothelial Barrier Dysfunction by Necroptotic Cell Death. American Journal of Respiratory Cell and Molecular Biology. American Journal of Respiratory Cell and Molecular Biology. 2017 Apr 19. Epub ahead of print. PMID: 28421813

Zaid Shakir, MD 2016-18
Pulmonary/Critical Care Medicine, University of Illinois at Chicago

Zeng, Zhenguo; Chen, Weiguo; Moshensky, Alexander; Shakir, Zaid; Khan, Raheel; Crotty-Alexander, Laura; Ware, Lorraine B.; Aldaz, Marcelo; Jacobson, Jeffrey R.; Dudek, Steven M.; Natarajan, Vishwanathan; Machado, Roberto F.; Singla, Sunit. Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS. Am J Respir Cell Mol Bio. 2021 Jan;64(1):89-99. PMID: 33058734

Singla, Sunit; Shakir, Zaid; Gomes, Marta T.; Jones, Nicole M.; Natarajan, Vishwanathan; Machado, Roberto F. Cigarette Smoke Exposure Induces Loss of Lung WWOX Expression Which Is Associated with Increased Vascular Leak During ARDS. Am J Respir Crit Care Med 2018;197: A2471.

Students (MD, PhD, Undergraduate):
Amulya Gampa, MD Medical Student Summer, 2013

University of Illinois at Chicago

Chief resident at University of Chicago

Singla, Sunit; Chen, Jiwang; Sethuraman, Shruthi; Sysol, Justin R.; Gampa, Amulya; Zhao, Shuangping; Machado, Roberto F. Loss of Lung WWOX Expression Causes Neutrophilic Inflammation. AJP: Lung Cellular and Molecular Physiology. 2017 Mar 10. Epub ahead of print. PMID: 28283473

Shruthi Sethuraman Undergraduate Summer, 2016
Ohio State University

Went on to work in the labs of John Christman, MD and Megan Ballinger, PhD
Presented at ATS in 2018
Now medical student at Ohio State University

Singla, Sunit; Chen, Jiwang; Sethuraman, Shruthi; Sysol, Justin R.; Gampa, Amulya; Zhao, Shuangping; Machado, Roberto F. Loss of Lung WWOX Expression Causes Neutrophilic Inflammation. AJP: Lung Cellular and Molecular Physiology. 2017 Mar 10. Epub ahead of print. PMID: 28283473

Collaborators
Laura E. Crotty Alexander, MD
Associate Professor of Medicine
University of California, San Diego

C. Marcelo Aldaz, MD/PhD
Professor of Medicine
MD Anderson
University of Texas

Roberto F. Machado, MD
Professor of Medicine
Indiana University

Jeffrey D. Hasday, MD
Professor of Medicine
University of Maryland

Lorraine B. Ware, MD
Professor of Medicine
Vanderbilt University

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