title: Epidermal growth factor receptor (EGFR) regulates mechanical ventilation-induced lung injury in mice.
abstract: Mechanical ventilation (MV) is used as therapy to support critically ill patients; however, the mechanisms by which MV induces lung injury and inflammation remain unclear. Epidermal growth factor receptor (EGFR)-mediated signaling plays a key role in various physiologic and pathologic processes, which include those modulated by mechanical and shear forces, in various cell types. We hypothesized that EGFR-activated signaling plays a key role in ventilator-induced lung injury and inflammation (VILI). To test this hypothesis, we assessed lung vascular and alveolar permeability as well as inflammation, which are cardinal features of VILI, in mice treated with the EGFR inhibitor AG1478. Inhibition of EGFR activity greatly diminished MV-induced lung alveolar permeability and neutrophil accumulation in the bronchoalveolar lavage (BAL) fluid, as compared with vehicle-treated controls. Similarly, AG1478 inhibition diminished lung vascular leak (as assessed by Evans blue extravasation), but it did not affect interstitial neutrophil accumulation. Inhibition of the EGFR pathway also blocked expression of genes induced by MV. However, intratracheal instillation of EGF alone failed to induce lung injury. Collectively, our findings suggest that EGFR-activated signaling is necessary but not sufficient to produce acute lung injury in mice.
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Division of Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: Bierman
authors.forename: Adi
authors.initials: A
authors.lastname: Yerrapureddy
authors.forename: Narsa M
authors.initials: NM
authors.lastname: Reddy
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hassoun
authors.forename: Sekhar P
authors.initials: SP
authors.lastname: Reddy
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007442:Intubation, Intratracheal; D051379:Mice; D008815:Mice, Inbred Strains; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011799:Quinazolines; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology; D055397:Ventilator-Induced Lung Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D012122:Ventilators, Mechanical / Q000009:adverse effects*
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D017027:Protein Tyrosine Phosphatases