title: Endothelial MKK3 is a critical mediator of lethal murine endotoxemia and acute lung injury.
abstract: Sepsis is a leading cause of intensive care unit admissions, with high mortality and morbidity. Although outcomes have improved with better supportive care, specific therapies are limited. Endothelial activation and oxidant injury are key events in the pathogenesis of sepsis-induced lung injury. The signaling pathways leading to these events remain poorly defined. We sought to determine the role of MAPK kinase 3 (MKK3), a kinase of the p38 group, in the pathogenesis of sepsis. We used a murine i.p. LPS model of systemic inflammation to mimic sepsis. Lung injury parameters were assessed in lung tissue and bronchoalveolar lavage specimens. Primary lung endothelial cells were cultured and assessed for mediators of inflammation and injury, such as ICAM-1, AP-1, NF-κB, and mitochondrial reactive oxygen species. Our studies demonstrate that MKK3 deficiency confers virtually complete protection against organ injury after i.p. LPS. Specifically, MKK3(-/-) mice were protected against acute lung injury, as assessed by reduced inflammation, mitochondrial reactive oxygen species generation, endothelial injury, and ICAM-1 expression after LPS administration. Our results show that endothelial MKK3 is required for inflammatory cell recruitment to the lungs, mitochondrial oxidant-mediated AP-1, NF-κB activation, and ICAM-1 expression during LPS challenge. Collectively, these studies identify a novel role for MKK3 in lethal LPS responses and provide new therapeutic targets against sepsis and acute lung injury.
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520-8057, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Mannam
authors.forename: Xuchen
authors.initials: X
authors.lastname: Zhang
authors.forename: Peiying
authors.initials: P
authors.lastname: Shan
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Shinn
authors.forename: Yitao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Patty J
authors.initials: PJ
authors.lastname: Lee
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D019446:Endotoxemia / Q000201:enzymology* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000473:pathology; D048371:MAP Kinase Kinase 3 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018375:Neutrophil Activation; D010538:Peritonitis / Q000139:chemically induced / Q000201:enzymology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011828:Radiation Chimera; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000201:enzymology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; C482199:lipopolysaccharide, E coli O55-B5; D018799:Intercellular Adhesion Molecule-1; D048371:MAP Kinase Kinase 3; C482531:Map2k3 protein, mouse