Acute lung injury (ALI) is a common cause of respiratory failure in critically ill adults, with an incidence of nearly 200,000 cases/year in the US alone and a mortality of 30-40%.1 ALI frequently follows major trauma, which is itself the leading cause of mortality nationally between the ages of 1 and 44;2 further, the development of ALI following trauma increases mortality by 3-fold.3 We recently discovered that both active smoking and moderate to heavy secondhand smoke exposure are associated with a nearly 3-fold increase in the odds of developing ALI after severe blunt trauma, independent of alcohol abuse. In the research proposed here, we will test the central hypothesis that both active smoking and secondhand smoke exposure prior to trauma predispose patients to develop ALI via injury to the lung epithelium and endothelium and enhanced susceptibility to infection. We will use the infrastructure of our established, ongoing prospective cohort of severely injured blunt trauma patients at San Francisco General Hospital to collect the necessary clinical data and biologic specimens in 600 new patients to study three specific aims. For all aims, both active and passive cigarette smoke exposure will be rigorously quantified by well-validated biomarkers: specifically, plasma cotinine and urine total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL).
In Aim 1, we will test the association between low-level secondhand smoke exposure and susceptibility to ALI after severe blunt trauma, since our prior studies were not large enough to address this level of exposure, which has major relevance to public health since it remains common in the US and internationally.
In Aim 2, we will determine the extent to which active smoking and/or secondhand smoke exposure prime patients to develop ALI via endothelial and lung epithelial injury. Endothelial and lung epithelial injury will be quantified by measurement of specific, previously studied and validated protein biomarkers in plasma and bronchoalveolar lavage.
In Aim 3, we will determine the extent to which active smoking and/or secondhand smoke exposure prime patients to develop ALI via enhanced susceptibility to infection, as reflected by changes in the lung microbiome. Our research group is well-qualified to conduct this research by virtue of our expertise in enrolling cohorts of severely injured trauma patients, measuring biomarkers of cigarette smoke exposure and of lung injury, characterizing the microbiome, and our history of successful collaboration. This project will significantly advance the field of ALI research by providing insight into how cigarette smoke primes patients to develop ALI, laying the groundwork for targeted and/or preventative therapies. In addition, it will likely have important public health implications regarding the regulation of secondhand smoke exposure. Our approach is especially innovative because of its focus on chronic environmental influences on the etiology of ALI, which have not been well studied;the use of biomarkers to measure exposure in critically ill subjects;its potential implications for prevention of ALI, a major priority of a recent NHLBI Working Group;and the insights it will provide into the effects of cigarette smoke exposure on the lung microbiome.

Public Health Relevance

Acute lung injury remains a common and frequently fatal cause of acute respiratory failure in critically ill patients, with no specific preventative strategies or therapies available. Studying the role of cigarette smoke exposure in the development of acute lung injury may help develop new therapies, including preventative approaches, and will provide further rationale and support for public health measures to eliminate passive and active cigarette smoke exposure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL110969-01
Application #
8212616
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Harabin, Andrea L
Project Start
2011-12-15
Project End
2016-11-30
Budget Start
2011-12-15
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$386,250
Indirect Cost
$136,250
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Robles, Anamaria J; Kornblith, Lucy Z; Hendrickson, Carolyn M et al. (2018) Health Care Utilization and the Cost of Post-Traumatic ARDS Care. J Trauma Acute Care Surg :
Moazed, Farzad; Hendrickson, Carolyn; Nelson, Mary et al. (2018) Platelet aggregation after blunt trauma is associated with the acute respiratory distress syndrome and altered by cigarette smoke exposure. J Trauma Acute Care Surg 84:365-371
Robles, Anamaria J; Kornblith, Lucy Z; Hendrickson, Carolyn M et al. (2018) Health care utilization and the cost of posttraumatic acute respiratory distress syndrome care. J Trauma Acute Care Surg 85:148-154
Kornblith, Lucy Z; Robles, Anamaria J; Conroy, Amanda S et al. (2018) Perhaps it's not the platelet: Ristocetin uncovers the potential role of von Willebrand factor in impaired platelet aggregation following traumatic brain injury. J Trauma Acute Care Surg 85:873-880
Panzer, Ariane R; Lynch, Susan V; Langelier, Chaz et al. (2018) Lung Microbiota Is Related to Smoking Status and to Development of Acute Respiratory Distress Syndrome in Critically Ill Trauma Patients. Am J Respir Crit Care Med 197:621-631
Ware, Lorraine B; Zhao, Zhiguo; Koyama, Tatsuki et al. (2017) Derivation and validation of a two-biomarker panel for diagnosis of ARDS in patients with severe traumatic injuries. Trauma Surg Acute Care Open 2:e000121
Zhao, Zhiguo; Wickersham, Nancy; Kangelaris, Kirsten N et al. (2017) External validation of a biomarker and clinical prediction model for hospital mortality in acute respiratory distress syndrome. Intensive Care Med 43:1123-1131
Famous, Katie R; Delucchi, Kevin; Ware, Lorraine B et al. (2017) Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy. Am J Respir Crit Care Med 195:331-338
Moazed, Farzad; Calfee, Carolyn S (2017) The Canary in the Coal Mine Is Coughing: Electronic Cigarettes and Respiratory Symptoms in Adolescents. Am J Respir Crit Care Med 195:974-976
Hendrickson, Carolyn M; Abbott, Jason; Zhuo, Hanjing et al. (2017) Higher mini-BAL total protein concentration in early ARDS predicts faster resolution of lung injury measured by more ventilator-free days. Am J Physiol Lung Cell Mol Physiol 312:L579-L585

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