title: TAT-HSP70 Attenuates Experimental Lung Injury.
abstract: Sepsis, a poorly understood syndrome of disordered inflammation, is the leading cause of death in critically ill patients. Lung injury, in the form of acute respiratory distress syndrome (ARDS), is the most common form of organ injury in sepsis. The heat shock response, during which heat shock proteins (HSPs) are expressed, is an endogenous mechanism to protect cells from injury. We have found that the abundance of pulmonary HSP70 is not increased after cecal ligation and double puncture (CLP) in a rat model of sepsis-induced ARDS. Using the HIV-1 trans-activator of transcription (TAT) cell-penetrating protein, we enhanced HSP70 protein abundance in the lung. We found that intratracheal administration of HSP70 using the TAT methodology, just after CLP (CLP-TAT-HSP70), when compared with treatment with phosphate buffered saline (CLP-phosphate buffered saline), significantly increased HSP70 abundance in the lung 24 and 48 h after surgery. Treatment of septic rats with TAT-HSP70 increased HSP70 abundance in histologically normal and abnormal lung regions. In addition, TAT-HSP70 treatment significantly decreased the levels of macrophage inflammatory protein 2 and cytokine-induced neutrophil chemoattractant 1 24 h after CLP. The TAT-HSP70 treatment reduced myeloperoxidase abundance 48 h after CLP and attenuated histological evidence of inflammation at both 24 and 48 h. Administration of TAT-HSP70 also improved 48-h survival in this rat model of sepsis. Thus, intratracheal administration of TAT-HSP70 increased HSP70 abundance in the lung and attenuated the lung injury. Enhancing pulmonary HSP70 using TAT is a novel potential therapeutic strategy for the treatment of ARDS that will be explored further.
authors: *Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine; †University of Pennsylvania School of Nursing; ‡Biostatistics Consulting Unit, Office of Nursing Research, University of Pennsylvania; §Center for Inflammation, Translational and Clinical Lung Research; and ∥Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors: M Melanie
authors: MM
authors: Lyons
authors: Nichelle N
authors: NN
authors: Raj
authors: Jesse L
authors: JL
authors: Chittams
authors: Laurie
authors: L
authors: Kilpatrick
authors: Clifford S
authors: CS
authors: Deutschman
mesh_terms: D000818:Animals; D054426:Chemokine CXCL2 / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000627:therapeutic use*; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D055370:Lung Injury / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate
chemical_list: D054426:Chemokine CXCL2; D018840:HSP70 Heat-Shock Proteins; D016209:Interleukin-8; D009195:Peroxidase