Wenxi Gao1, Jinbo Zhao2, Hyunhee Kim1, Shuyun Xu3, Manyin Chen3, Xiaohui Bai3, Hiroaki Toba3, Hae-Ra Cho1, Haibo Zhang4, Shaf Keshavjeel5, Mingyao Liu6. 1. Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network; Department of Physiology, University of Toronto, Toronto, Ontario, Canada. 2. Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network; Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Shaanxi, China. 3. Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network. 4. Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, Faculty of Medicine. 5. Institute of Medical Science, Faculty of Medicine; Department of Surgery, University of Toronto, Toronto, Ontario, Canada. 6. Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, Faculty of Medicine; Department of Surgery, University of Toronto, Toronto, Ontario, Canada. Electronic address: mingyao.liu@utoronto.ca.
Abstract
BACKGROUND: Pulmonary ischemia-reperfusion (IR)-induced lung injury is a severe complication that increases the likelihood of primary graft dysfunction and early death after lung transplantation. Inflammatory cytokine release and cell death play a critical role in the development of IR-induced lung injury. α1-Antitrypsin (A1AT) is a protease inhibitor clinically used for the treatment of A1AT-deficiency emphysema. On the basis of a literature review, we hypothesize that A1AT may have the potential to reduce IR-induced lung injury through its anti-inflammatory and anti-apoptotic effects. METHODS: A human pulmonary cell culture model was used to simulate IR processes in lung transplantation. Effects of A1AT on cell death and cytokine production were examined. A rat pulmonary IR model, in which the left pulmonary hilum was clamped for 90 minutes, followed by reperfusion for 2 hours, was used to determine the effects of A1AT on acute lung injury, function, cell death, and inflammatory response. RESULTS: A1AT significantly inhibited cell death and inflammatory cytokine release dose-dependently in vitro and significantly improved lung oxygenation and lung mechanics and reduced pulmonary edema in vivo. Moreover, A1AT inhibited neutrophil infiltration in the lung and reduced cell death and significantly reduced IR-induced inflammatory mediators in plasma, including interleukin (IL)-1α, IL-4, IL-12p70, monocyte chemotactic protein 1, and tumor necrosis factor-α. CONCLUSIONS: Considering its current clinical use, our findings indicate that administration of A1AT may be an effective and safe therapy for the treatment of IR injury in human lung transplantation.
BACKGROUND: Pulmonary ischemia-reperfusion (IR)-induced lung injury is a severe complication that increases the likelihood of primary graft dysfunction and early death after lung transplantation. Inflammatory cytokine release and cell death play a critical role in the development of IR-induced lung injury. α1-Antitrypsin (A1AT) is a protease inhibitor clinically used for the treatment of A1AT-deficiency emphysema. On the basis of a literature review, we hypothesize that A1AT may have the potential to reduce IR-induced lung injury through its anti-inflammatory and anti-apoptotic effects. METHODS: A human pulmonary cell culture model was used to simulate IR processes in lung transplantation. Effects of A1AT on cell death and cytokine production were examined. A rat pulmonary IR model, in which the left pulmonary hilum was clamped for 90 minutes, followed by reperfusion for 2 hours, was used to determine the effects of A1AT on acute lung injury, function, cell death, and inflammatory response. RESULTS:A1AT significantly inhibited cell death and inflammatory cytokine release dose-dependently in vitro and significantly improved lung oxygenation and lung mechanics and reduced pulmonary edema in vivo. Moreover, A1AT inhibited neutrophil infiltration in the lung and reduced cell death and significantly reduced IR-induced inflammatory mediators in plasma, including interleukin (IL)-1α, IL-4, IL-12p70, monocyte chemotactic protein 1, and tumor necrosis factor-α. CONCLUSIONS: Considering its current clinical use, our findings indicate that administration of A1AT may be an effective and safe therapy for the treatment of IR injury in human lung transplantation.
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