Therapeutic potential of recombinant thrombomodulin for lung injury after pneumonectomy via inhibition of high-mobility group box 1 in mice

Abstract

Surgical acute respiratory distress syndrome (ARDS) is an extremely critical condition which may occur after major lung resection. Despite advances in minimally invasive surgical procedures and progress in the therapeutic management of this disease, prognosis remains poor. In this study, we investigated the contribution of high-mobility group box 1 (HMGB1) in a surgical ARDS model and evaluated the possible therapeutic effect of recombinant thrombomodulin (rTM) for the treatment of surgical ARDS. C57BL/6J mice underwent left pneumonectomy. rTM was injected at 12 hours before surgery, followed by 12 hours for 3 days after surgery. Lipopolysaccharide (LPS) was administered at 2 hours after surgery. We conducted a histologic analysis and measured HMGB1, IL-6, IL-1β, and TNF-α in bronchoalveolar lavage fluid on day 3 after pneumonectomy. Data were compared between the treatment groups. On histologic analysis, left pneumonectomy followed by LPS administration induced both severe inflammatory cellular infiltration and alveolar wall congestion with hemorrhage. rTM administration rescued these histologic changes. The level of HMGB1, IL-6, IL-1β, and TNF-α in bronchoalveolar lavage fluid was significantly increased by LPS administration after pneumonectomy and significantly decreased by rTM administration with LPS and pneumonectomy (p < 0.001). Also, LPS alone showed no statistical differences in HMGB1 or proinflammatory cytokine level compared with pneumonectomy (PNX) group. In addition, the survival outcome was also improved by rTM administration. LPS administration after left pneumonectomy could induce the severe lung injury. PNX and LPS have similar contribution to this model and may play a synergistic role in this process. rTM may have the potential therapeutic effect for surgical ARDS via suppression of HMGB1 and the secretion of proinflammatory cytokines induced by the administration of LPS after left pneumonectomy.