ARDS, acute lung injury (ALI) and septic shock are commonly encountered conditions in the intensive care unit, with relatively high mortality rates despite advances in treatment. Research into these conditions often focuses on the role of inflammatory cells. However, little is known about why some patients progress to ARDS or septic shock while others with the same risk factors do not.
Our primary study proposes that genes play a role in the development of these conditions. We investigate this hypothesis through a prospective cohort of patients admitted to Massachusetts General Hospital and Beth Israel Deaconess Medical Center intensive care units with known risk factors for development of ARDS. During this study, which began in 1998, we expect to enroll about 6,800 patients.
The major research interests of our medical director, David Christiani, MD, MPH, are gene-environment interactions in acute and chronic illness. He has been active in developing new methods for assessing health effects after exposure to pollutants, incorporating genetic studies in environmental health and introducing genetic studies into the critical-care setting. His interest in global environmental health dates back 30 years, and he has led or co-led international collaborative studies in Asia, Africa and Latin America.
A staff physician in the Mass General Pulmonary and Critical Care Unit, Dr. Christiani is also a professor of medicine at Harvard Medical School and the Elkan Blout Professor of Environmental Genetics at the Harvard School of Public Health. In addition, he directs the environmental and occupational medicine section of the Mass General Division of Pulmonary and Critical Care Medicine.
Candidate gene analysis in acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) for risk and outcome
Our studies were among the first to demonstrate a role for genetic susceptibility to ALI and its more severe form, ARDS.
Genome-wide association study of patients with ARDS
This work expands upon our previous candidate gene variation work in considering all possible genetic variants throughout the human genome in a comprehensive analysis of risk and outcome. This project is part of a large consortium effort that will involve multiple centers and correlate genetic markers with a multiplex assay of circulating plasma protein biomarkers.
Genetic predictors of acute kidney injury in our cohort
Acute kidney injury is a major complication of sepsis, ALI and ARDS in the intensive care unit and accounts for significant morbidity and mortality. We are aiming to characterize genetic predictors to improve medical management, understand mechanistic pathways better and possibly elucidate targets for pharmacologic intervention.
Genetic predictors of infectious vs. noninfectious causes of ALI
Our studies have shown there are different genetic variants that may predispose individuals to different kinds of ALI.
Metabolic factors and adipokines and the risks and outcomes of patients with ARDS
Body mass index, and hence adiposity, affects ARDS and ALI risk. Adiposity is associated with systemic inflammation, and adipose tissue acts as an active endocrine organ, secreting pro-inflammatory hormones like adipokines. We are assessing actively the roles of these circulating proteins in the risk and outcomes in ARDS/ALI.
Gene expression studies of patients with and without ARDS
We have identified a novel marker that is likely key in the mechanism of ARDS development and progress, the PI3 (elafin) protein. Plasma levels of this protein predict development of ARDS in persons at risk, and genetic polymorphisms in the gene coding for this protein support a role for genetic susceptibility to ARDS in at-risk individuals.
Evaluating the role of cardiac biomarkers in diagnosis and prognostication of patients with sepsis and ARDS
We have found that plasma markers of myocardial injury—even when in the clinically normal range and in patients who do not exhibit clinical evidence of myocardial damage—show a dose-response relationship with mortality outcome in ARDS. This suggests an important role for preclinical cardiac effects in patients with ALI.
Exploring the role of exhaled breath condensate metabonomics as a biomarker for lung epithelial injury in mechanically ventilated patients
We are examining the role of lung metabolic profiling on a simple, noninvasive method of collecting expired breath condensate from intubated patients with and without ALI/ARDS.
Meyer NJ, Li M, Feng R, Bradfield J, Gallop R, Bellamy S, Fuchs BD, Lanken PN, Albelda SM, Rushefski M, Aplenc R, Abramova H, Atochina-Vasserman EN, Beers MF, Calfee CS, Cohen MJ, Pittet JF, Christiani DC, O'Keefe GE, Ware LB, May AK, Wurfel MM, Hakonarson H, Christie JD. ANGPT2 Genetic Variant is Associated with Trauma-Associated Acute Lung Injury and Altered Plasma Angiopoietin-2 Isoform Ratio. Am J Respir Crit Care Med. 2011 Jan 21. [Epub ahead of print] PubMed PMID: 21257790.
Sheu CC, Gong MN, Zhai R, Chen F, Bajwa EK, Clardy PF, Gallagher DC, Thompson BT, Christiani DC. Clinical characteristics and outcomes of sepsis-related vs non-sepsis-related ARDS. Chest. 2010 Sep;138(3):559-67. Epub 2010 May 27. PubMed PMID: 20507948; PubMed Central PMCID: PMC2940067.
Sheu CC, Zhai R, Wang Z, Gong MN, Tejera P, Chen F, Su L, Thompson BT, Christiani DC. Heme oxygenase-1 microsatellite polymorphism and haplotypes are associated with the development of acute respiratory distress syndrome. Intensive Care Med. 2009 Aug;35(8):1343-51. Epub 2009 Jun 13. PubMed PMID: 19526221; PubMed Central PMCID: PMC2758618.
Su L, Zhai R, Sheu CC, Gallagher DC, Gong MN, Tejera P, Thompson BT, Christiani DC. Genetic variants in the angiopoietin-2 gene are associated with increased risk of ARDS. Intensive Care Med. 2009 Jun;35(6):1024-30. Epub 2009 Mar 7. PubMed PMID: 19271210; PubMed Central PMCID: PMC2696283.
Tejera P, Wang Z, Zhai R, Su L, Sheu CC, Taylor DM, Chen F, Gong MN, Thompson BT, Christiani DC. Genetic polymorphisms of peptidase inhibitor 3 (elafin) are associated with acute respiratory distress syndrome. Am J Respir Cell Mol Biol. 2009 Dec;41(6):696-704. Epub 2009 Feb 27. PubMed PMID: 19251943; PubMed Central PMCID: PMC2784407.
Wang Z, Beach D, Su L, Zhai R, Christiani DC. A genome-wide expression analysis in blood identifies pre-elafin as a biomarker in ARDS. Am J Respir Cell Mol Biol. 2008 Jun;38(6):724-32. Epub 2008 Jan 18. PubMed PMID: 18203972; PubMed Central PMCID: PMC2396250.
Bajwa EK, Boyce PD, Januzzi JL, Gong MN, Thompson BT, Christiani DC. Biomarker evidence of myocardial cell injury is associated with mortality in acute respiratory distress syndrome. Crit Care Med. 2007 Nov;35(11):2484-90. PubMed PMID: 18084839.
Bajwa EK, Yu CL, Gong MN, Thompson BT, Christiani DC. Pre-B-cell colony-enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome. Crit Care Med. 2007 May;35(5):1290-5. PubMed PMID: 17414088.
Research Coordinator: Andrea Shafer, MPH