Lyons M Melanie, Raj Nichelle N, Chittams Jesse L, Kilpatrick Laurie, Deutschman Clifford S
*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.
Shock. 2015 Jun;43(6):582-8. doi: 10.1097/SHK.0000000000000352.
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.
脓毒症是一种炎症紊乱但了解甚少的综合征，是重症患者死亡的主要原因。以急性呼吸窘迫综合征（ARDS）形式出现的肺损伤是脓毒症中最常见的器官损伤形式。热休克反应期间热休克蛋白（HSPs）表达，这是一种保护细胞免受损伤的内源性机制。我们发现在脓毒症诱导的ARDS大鼠模型中，盲肠结扎和双穿刺（CLP）后肺组织中HSP70的丰度并未增加。利用HIV-1转录反式激活因子（TAT）细胞穿透蛋白，我们提高了肺组织中HSP70蛋白的丰度。我们发现，在CLP后立即采用TAT方法气管内给予HSP70（CLP-TAT-HSP70），与用磷酸盐缓冲盐水治疗（CLP-磷酸盐缓冲盐水）相比，术后24小时和48小时肺组织中HSP70的丰度显著增加。用TAT-HSP70治疗脓毒症大鼠可增加组织学正常和异常肺区域中HSP70的丰度。此外，TAT-HSP70治疗在CLP后24小时显著降低了巨噬细胞炎性蛋白2和细胞因子诱导的中性粒细胞趋化因子1的水平。TAT-HSP70治疗在CLP后48小时降低了髓过氧化物酶的丰度，并在24小时和48小时减轻了炎症的组织学证据。给予TAT-HSP70也提高了该脓毒症大鼠模型48小时的生存率。因此，气管内给予TAT-HSP70增加了肺组织中HSP70的丰度并减轻了肺损伤。利用TAT增强肺组织中HSP70是一种治疗ARDS的新型潜在治疗策略，有待进一步探索。
