Interleukin-6 blockade, a potential adjunct therapy for post-burn hypermetabolism.
Interleukin-6 blockade, a potential adjunct therapy for post-burn hypermetabolism.
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DOI：
10.1096/fj.202100388r
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Jeschke MG
中科院分区：
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作者：
Barayan D;Abdullahi A;Vinaik R;Knuth CM;Auger C;Jeschke MG
严重烧伤仍然是全世界死亡和残疾的主要原因。尽管患者护理有所进步，但这种创伤引起的过度和不受控制的高代谢应激反应不可避免地影响到每个器官系统，导致大量发病率和死亡率。最近的证据表明，白细胞介素-6 （IL-6）是烧伤后高代谢的罪魁祸首。事实上，IL-6的基因缺失减轻了与不良临床结果相关的各种并发症，包括脂肪组织的不良重塑、恶病质和肝脏脂肪变性。因此，药物阻断IL-6可能是损伤后完全恢复代谢功能的更有利的治疗选择。为了验证这一点，我们在实验小鼠模型中使用经过验证的抗IL-6单克隆抗体（mAb）研究了阻断IL-6治疗烧伤后高代谢的安全性和有效性。在这里，我们显示每日给药抗il -6单抗可以防止烧伤引起的体重减轻（P < 0.0001），而对死亡率没有任何不利影响。在器官水平上，烧伤后使用IL-6阻滞剂抑制脂肪组织的产热激活（P < 0.01）及其相关的消耗（P < 0.05）。褐化诱导的脂肪分解减少（P < 0.0001）间接降低肝脂毒性（P < 0.01），改善肝功能障碍（P < 0.05）。重要的是，这种抗il -6药物的有益作用扩展到皮肤，反映在减少过多的胶原沉积（P < 0.001）和参与病理性纤维化和瘢痕形成的基因（P < 0.05）。总之，我们的研究结果表明，烧伤后IL-6阻断通过抑制关键免疫代谢器官的病理改变，导致全身高代谢的显著改善。这些发现支持了抗il -6干预的治疗潜力，以改善烧伤患者的护理、生活质量和生存率。
Severe burns remain a leading cause of death and disability worldwide. Despite advances in patient care, the excessive and uncontrolled hypermetabolic stress response induced by this trauma inevitably affects every organ system causing substantial morbidity and mortality. Recent evidence suggests interleukin-6 (IL-6) is a major culprit underlying post-burn hypermetabolism. Indeed, genetic deletion of IL-6 alleviates various complications associated with poor clinical outcomes including the adverse remodeling of adipose tissue, cachexia and hepatic steatosis. Thus, pharmacological blockade of IL-6 may be a more favorable treatment option to fully restore metabolic function after injury. To test this, we investigated the safety and effectiveness of blocking IL-6 for post-burn hypermetabolism using a validated anti-IL-6 monoclonal antibody (mAb) in our experimental murine model. Here, we show daily anti-IL-6 mAb administration protects against burn-induced weight loss (P < .0001) without any adverse effect on mortality. At the organ level, post-burn treatment with the IL-6 blocker suppressed the thermogenic activation of adipose tissue (P < .01) and its associated wasting (P < .05). The reduction of browning-induced lipolysis (P < .0001) indirectly decreased hepatic lipotoxicity (P < .01) which improved liver dysfunction (P < .05). Importantly, the beneficial effects of this anti-IL-6 agent extended to the skin, reflected by the decrease in excessive collagen deposition (P < .001) and genes involved in pathologic fibrosis and scarring (P < .05). Together, our results indicate that post-burn IL-6 blockade leads to significant improvements in systemic hypermetabolism by inhibiting pathological alterations in key immunometabolic organs. These findings support the therapeutic potential of anti-IL-6 interventions to improve care, quality of life, and survival in burned patients.