Functional Genomic Insights into Acute Lung Injury: Role of Ventilators and Mechanical Stress

Abstract

Acute lung injury (ALI) is a complex and devastating illness, often occurring in the setting of sepsis and trauma. Despite recent advances in the understanding and treatment of ALI, pathogenic mechanisms and genetic modifiers in ALI remain incompletely understood. Furthermore, there has been increasing interest in the identification of genetic variations that contribute to ALI susceptibility and severity in order to gain unique insights into ALI pathogenesis and to design novel treatment strategies. However, the sporadic nature of ALI and the lack of family-based cohort studies preclude conventional genomic approaches such as linkage mapping (or "positional cloning"). We have used a "candidate gene approach" with extensive gene expression profiling studies in animal (rat, murine, canine) and human models of ALI to identify potential ALI candidate genes associated with sepsis and ventilator-associated lung injury. These studies, when combined with innovative in silico bioinformatics approaches, revealed both novel (pre-B-cell colony enhancing factor, myosin light chain kinase) and previously identified (interleukin 6, macrophage migration inhibitory factor) gene candidates. Subsequent single nucleotide polymorphism discovery and genotyping studies revealed polymorphisms that demonstrate an influence on ALI susceptibility in patients. These studies indicate that the candidate gene approach is a robust strategy to provide novel insights into the genetic basis of ALI, and the identification of potentially novel therapeutic targets.Keywords: single nucleotide polymorphism; interleukin 6; pre-B-cell colony enhancing factor Acute lung injury (ALI) is a common and devastating illness in patients with sepsis, pneumonia, or trauma, and carries an annual mortality rate of 30 to 50% (1). Marked by profound inflammation, increased vascular permeability, and alveolar flooding, the acute respiratory failure that is associated with ALI invariably requires mechanically assisted ventilation. Despite advances in care for patients with ALI, the development of sophisticated hemodynamic monitoring technologies, and new insights into the pathogenesis underlying sepsis and ALI, there remains a significant gap in the full translation of this progress into increased ALI survival (2). Furthermore, improved understanding of ALI at both the molecular and population level has not reconciled the heterogeneity in patient susceptibility to ALI or ALI outcomes. Until recently, studies focused on understanding the molecular basis of complex disorders such as ALI were limited to a gene-by-gene approach. However, the capacity for high-throughput sequencing coupled with the mapping of the human genome heralded additional revolutionary technologic breakthroughs with tools for a large-scale analysis of the genome, including rapid, high-throughput gene expression profiling and genotyping (3, 4). Access to the complete genome sequences of prokaryotes, eukaryotic model organisms, as well as the mouse, rat, and dog has sparked efforts to identify specific...

Recent advances in genetic predisposition to clinical acute lung injury

“…Sadly, this has not been the case for some of the devastating lung diseases, including ALI and ARDS. Consider that, based on an updated review of the literature on genetic associations with lung injury, only 31 genetic association studies have been published, and of those, associations between polymorphisms in only 21 genes and ALI/ARDS phenotypes have been confirmed (11,30,37,51,73,81), as summarized in Table 1.…”

“…With this backdrop, it is reasonable that many of the candidate genes studied to date fall within these specific pathways. Some of the most compelling associations have been between specific gene polymorphisms and susceptibility and/or outcomes of ALI in genes encoding surfactant proteins (SPs) (39,54,64,77); angiotensin converting enzyme (ACE) (2,48,60); proinflammatory cytokines [TNFA/TNFB (40), IL6 (31,61,73,87), IL8 (44), PBEF1 (10,97), MIF (32), and VEGF (66, 99)] and anti-inflammatory cytokine IL10 (38,83). The most replicated genes include IL6, SFTPB, and ACE.…”

“…Despite the fact that, in the last few years, there has been a number of studies focusing on the genetics of ALI (11,29,30,37,73,81), there remain significant challenges in elucidating the major genes involved in lung injury pathophysiology. First, ALI represents a continuum rather than a discreet group of phenotypes, and therefore lacks unique, readily measurable biomarkers for definitive diagnosis.…”

Genomic insights into acute inflammatory lung injury

“…17, 15, 19; mechanical ventilation/VALI, Refs. 15,18). Human and animal protocols were approved by the Institutional Review Boards.…”

Stretch-Induced Activation of AMP Kinase in the Lung Requires Dystroglycan

“…In many pulmonary diseases, including acute lung injury, asthma, chronic obstructive lung diseases, and pulmonary fibrosis, the mechanical forces exerted on the cells are altered, which results in the activation of a number of distinct signaling pathways. Some of these pathways may be protective, whereas others may exacerbate the underlying pathology (4)(5)(6).…”