Genomic insights into acute inflammatory lung injury

Abstract

Acute lung injury (ALI) is a devastating syndrome (usually associated with sepsis) that represents a major healthcare burden in the United States. We have focused our studies on unraveling the genetic underpinnings of this syndrome utilizing a candidate gene approach to identify novel genes for ALI susceptibility. Two novel genes identified by this approach include pre-B cell colony-enhancing factor (PBEF) and the gene for myosin light chain kinase (MLCK). PBEF protein levels were elevated in human bronchoalveolar lavage and serum samples from patients with ALI, and DNA sequencing identified two single nucleotide polymorphisms in the PBEF promoter (T-1001G, C-1543T) that were overrepresented in patients with sepsis-induced ALI. More recently, we found MLCK single polymorphisms and haplotypes to be associated with human ALI with unique variants observed in African-Americans with ALI. Thus genomic and genetic approaches represent powerful strategies in the identification of novel candidate genes and potential targets for ALI therapies. acute respiratory distress syndrome; mechanical ventilation; single nucleotide polymorphisms; haplotype ACUTE LUNG INJURY (ALI) and acute respiratory distress syndrome (ARDS) are inflammatory lung syndromes characterized by diffuse alveolar infiltration, hypoxemia, respiratory failure, and deaths due to multiorgan failure. Mortality rates in ARDS, the most severe ALI clinical scenario, range from 34 to 58% (13) with ϳ150,000 -200,000 ALI cases per year in the United States (27) and an incidence of 17-34 cases/100,000 people per year in Europe, Australia, and other developed countries. Thus ALI and ARDS constitute a major healthcare burden due to the intensive and often prolonged intensive care unit (ICU) hospitalizations. In addition to these epidemiologic studies, race and gender differences in ARDS deaths in the United States over the past several decades have clearly demonstrated an increase in incidence and mortality due to sepsis and ALI in African-Americans when compared with Caucasians (16).ALI is usually caused by sepsis, acid inhalation, or trauma with mechanical ventilation, an intervention strategy commonly used in the ICU to treat ALI, potentially exacerbating ALI pathophysiology and reducing survival if excessive (22,24,10). The hallmarks for ALI, i.e., cellular and spatial heterogeneity, profound high permeability, leukocyte influx, and lung edema, are often augmented by mechanical ventilation in animal models of ALI (30) and are contributing factors for death due to multiorgan failure (23).Genetics/genomics. Over the past several decades, a lingering issue of concern for critical care physicians has been the enormous heterogeneity in the outcomes observed in the care of the ALI/ARDS patient. Why do some conventionally ventilated ARDS patients recover quickly with rapid extubation, whereas other ARDS patients progress to multiorgan failure and death? What underlies the now recognized healthcare disparity observed in ALI and sepsis outcomes in AfricanAmericans? Although...

Involvement of visfatin in palmitate-induced upregulation of inflammatory cytokines in hepatocytes

“…Serum IL-6 and TNF-α levels were higher in ZDF rats, and their mRNA expression in liver tissue was significantly increased. Some reports have suggested that both tissue and circulating visfatin levels are increased in inflammatory disorders [9][10][11]. It has been shown that FFAs play a significant role in hepatic inflammation and insulin resistance [4] and that the liver secretes visfatin [6,7].…”

“…It has been shown that visfatin has nicotinamide adenine dinucleotide (NAD) biosynthetic activity; and thus, visfatin is also known as nicotinamide phosphoribosyltransferase, the rate-limiting enzyme that converts nicotinamide to nicotinamide mononucleotide, a NAD precursor [8]. Recent studies have demonstrated that visfatin acts as a proinflammatory cytokine and that its expression is increased in inflammatory conditions such as acute lung injury, sepsis, and rheumatoid arthritis [9][10][11]. Visfatin is associated with obesity and obesity-related insulin resistance, type 2 diabetes mellitus, and metabolic syndrome [12][13][14].…”

Essential Role of Pre–B-Cell Colony Enhancing Factor in Ventilator-induced Lung Injury

“…We previously used genomics-intensive approaches to identify potential ALI and VILI susceptibility candidate genes (11,12). We determined that the gene encoding pre-B-cell colony enhancing factor (PBEF), a proinflammatory cytokine expressed in amniotic membranes during gestation (13), represented a potential VILI candidate gene and novel biomarker in sepsis and ALI (1).…”

Adipocytokines in Severe Sepsis and Septic Shock

“…It exerts chemotactic activity and up-regulates the serum levels of other pro-inflammatory cytokines [110]. Garcia and Vinasco demonstrated a crucial role for PBEF in acute lung injury (ALI), which is usually caused by sepsis [111]. In these critical ill patients they found elevated concentrations of PBEF in bronchoalveolar lavage and serum.…”