Translational Research
Volume 152, Issue 6 , Pages 255-256, December 2008

Stretching the Search for Therapeutic Targets in Acute Lung Injury

University of Chicago, Chicago, Ill

published online 13 November 2008.

Article Outline

 

Genome-wide microarray analyses have sparked efforts to identify specific gene expression patterns that may help to diagnose, prognosticate, guide therapy, or even contribute to our overall understanding of human diseases, including human lung disorders. Acute lung injury (ALI), which is a major cause of morbidity and mortality in critically ill patients,1 is an enigmatic but devastating consequence of systemic inflammatory conditions such as sepsis that affects ~200,000 patients per year in the United States and accounts for ~75,000 deaths. A defining feature of ALI is the disruption of both the endothelial cell barrier that lines the pulmonary vasculature and the epithelial cell barrier, which results in leakage of fluid, protein, and cells into the airspaces of the lungs.2 Many bioactive agonists and their receptors contribute to endothelial/epithelial barrier regulation via direct effects on the integrity of tight junctions as well as cell–cell and cell–matrix adhesions.3 Attempts to identify ALI-associated candidate genes have used in silico bioinformatic approaches4, 5 or functional pathway analyses, such as signaling paradigms driven by receptor ligation that result in cytoskeletal rearrangement and increased lung permeability.6, 7 A final approach has been the employment of genome-wide microarrays to identify genes expressed differentially in rodent models of high-tidal-volume ventilation.8, 9, 10, 11 Robust alterations in gene expression were noted with upregulation of inflammatory cytokines, transcription factors (such as Egr1, c-Jun, and Nrf2), and tyrosine kinase growth factor receptors, such as vascular epidermal growth factor receptor, epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), which are factors of obvious significance in ventilator-induced lung injury (VILI) and ALI.4, 5, 8, 9, 10, 11

In this issue of Translational Research, Bierman et al present evidence that the EGFR is an important contributor to VILI and inflammation. Mice treated with AG1478, which is a compound that inhibits EGFR kinase activity and HER2-neu and PDGFR kinase activity at higher concentrations,12, 13 diminishes mechanical VILI-induced lung alveolar permeability and neutrophil accumulation. Although the EGFR is expressed at very low, often undetectable levels in normal endothelium,14, 15 AG1478 treatment seems to inhibit significantly the lung vascular leak induced by the increased mechanical stress of VILI. Importantly, this VILI seems to be independent of EGF stimulation, which indicates a potential transactivation mechanism of the EGFR. This study illustrates how the EGFR, which is a member of the ErbB family that consists of EGFR (HER-1/ErbB1), ErbB2 (HER2-neu), ErbB3 (HER3), and ErbB4 (HER4), can contribute to ALI. Increasing literature suggests that the tyrosine growth factor receptor transactivation (ligand-independent activation), which includes ErbB receptor tyrosine kinases, is important for effective signal transduction following multiple agonists, including prostaglandin E2, bradykinin, hyaluronan, lysophosphatidic acid, and sphingosine 1-phosphate.16, 17, 18, 19

Advances in genomic discovery have heralded the era of molecular medicine and have revolutionized translational biomedical research as well as increased the understanding of alterations in organ function produced by disease processes that require carefully orchestrated spatial and temporal expression of tens to hundreds of genes. Characterization of genes abnormally expressed in diseased tissues provides the promise for the identification of novel genes that serve as biomarkers, diagnostic markers, prognostic indicators, and targets for therapeutic intervention. The discovery by Bierman et al that inhibition of EGFR tyrosine kinase activity attenuates ALI may have significant clinical implications. Effective therapies to reverse the vascular damage observed in ALI are ineffective (exogenous surfactant, corticosteroids, prostacyclin, antioxidants, etc).20, 21 Exploration of treatments involving EGFR inhibitors, like those employed by Bierman et al, are a novel and potentially therapeutic approach to inhibiting the morbidity and mortality of ALI/ARDS.

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References 

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PII: S1931-5244(08)00247-8

doi:10.1016/j.trsl.2008.10.006

Translational Research
Volume 152, Issue 6 , Pages 255-256, December 2008

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