title: Activation of the heat shock response attenuates the interleukin 1β-mediated inhibition of the amiloride-sensitive alveolar epithelial ion transport.
abstract: Acute lung injury (ALI) is a clinical syndrome characterized by hypoxia, which is caused by the breakdown of the alveolar capillary barrier. Interleukin 1β (IL-1β), a cytokine released within the airspace in ALI, downregulates the α subunit of the epithelial sodium channel (αENaC) transcription and protein expression via p38 MAP kinase-dependent signaling. Although induction of the heat shock response can restore alveolar fluid clearance compromised by IL-1β following the onset of severe hemorrhagic shock in rats, the mechanisms are not fully understood. In this study, we report that the induction of the heat shock response prevents IL-1β-dependent inhibition of αENaC mRNA expression and subsequent channel function. Heat shock results in IRAK1 detergent insolubility and a disruption of Hsp90 binding to IRAK1. Likewise, TAK1, another client protein of Hsp90 and signaling component of the IL-1β pathway, is also detergent insoluble after heat shock. Twenty-four hours after heat shock, both IRAK1 and TAK1 are again detergent soluble, which correlates with the IL-1β-dependent p38 activation. Remarkably, IL-1β-dependent p38 activation 24 h after heat shock did not result in an inhibition of αENaC mRNA expression and channel function. Further analysis demonstrates prolonged preservation of αENaC expression by the activation of the heat shock response that involves inducible Hsp70. Inhibition of Hsp70 at 24 h after heat shock results in p38-dependent IL-1β inhibition of αENaC mRNA expression, whereas overexpression of Hsp70 attenuates the p38-dependent IL-1β inhibition of αENaC mRNA expression. These studies demonstrate new mechanisms by which the induction of the heat shock response protects the barrier function of the alveolar epithelium in ALI.
authors: Laboratory of Surgical Research, Department of Anesthesia, University of California, San Francisco, California, USA.
authors: Marybeth
authors: M
authors: Howard
authors: Jérémie
authors: J
authors: Roux
authors: Karen E
authors: KE
authors: Iles
authors: Byron
authors: B
authors: Miyazawa
authors: Sarah
authors: S
authors: Christiaans
authors: Naseem
authors: N
authors: Anjum
authors: Dale A
authors: DA
authors: Dickinson
authors: Arnaud
authors: A
authors: Goolaerts
authors: Michael A
authors: MA
authors: Matthay
authors: Jean Francois
authors: JF
authors: Pittet
mesh_terms: D055371:Acute Lung Injury / Q000517:prevention & control*; D000584:Amiloride / Q000494:pharmacology*; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000494:pharmacology; D062686:Epithelial Sodium Channel Blockers / Q000494:pharmacology*; D053503:Epithelial Sodium Channels / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000502:physiology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D053583:Interleukin-1beta / Q000502:physiology*; D060588:LIM Domain Proteins / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D011650:Pulmonary Alveoli / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020545:Respiratory Mucosa / Q000378:metabolism; D015854:Up-Regulation; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000584:Amiloride; D016227:Benzoquinones; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D018840:HSP70 Heat-Shock Proteins; D053592:Interleukin-1 Receptor-Associated Kinases; D053583:Interleukin-1beta; D060588:LIM Domain Proteins; D047029:Lactams, Macrocyclic; D020930:MAP Kinase Kinase Kinases; D012333:RNA, Messenger; D000099151:MAP Kinase Kinase Kinase 7; C490352:Tgfb1i1 protein, rat; C112765:tanespimycin