Imbalance of Th17/Tregs in rats with smoke inhalation-induced acute lung injury.

Smoke inhalation injury is generally defined as inhalation of thermal or chemical irritants1, with a high incidence of pulmonary complications and mortality in burn patients and soldiers2,3. Military operations are complex, dynamic, and always dangerous because of toxic industrial chemicals and materials such as gunpowder. In military activities, gunpowder is used to shield the soldiers, attack enemy or simulate battlefield environments. Gunpowder can generate large amounts of toxic gases and particles during explosion and combustion. Smoke inhalation is the leading cause of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), or even serious respiratory failure in military personnel. Despite decades of intense research, the molecular mechanisms involved in the pathogenesis of smoke inhalation-induced acute lung injury are poorly defined. It is generally believed that inflammatory cells and release of inflammatory mediators, especially neutrophils and macrophages, are mandatory in the pathological process of smoke inhalation-induced acute lung injury4,5. However, the role of adaptive immune cells in this disease is less well defined. A recent study indicated that lymphocyte-deficient mice were unable to increase neutrophils in response to lipopolysaccharide, suggesting that T lymphocytes may contribute to pulmonary inflammatory pathways in ALI6. Most recently, CD4+ T lymphocytes, especially regulatory T (Treg) cells and T helper (Th) 17 cells, have become an active topic of research in the pathogenesis or resolution of ALI/ARDS7,8,9,10,11. Both cell types are generated from naive T cells that require transforming growth factor (TGF)-β with opposing actions12. CD4+ CD25+ Foxp3+ Tregs plays an anti-inflammatory role mainly by contact-dependent suppression or releasing inhibitory cytokines such as IL-10 and TGF-β on other immune cells, including CD4+ and CD8+ T cells, B cells, natural killer (NK) cells and dendritic cells13. Reduced generation or deficient function of Tregs has been reported in a number of autoimmune diseases14. Notably, D’Alessio and colleagues’ study showed that Treg modifies innate immune responses during resolution of lung injury, suggesting its potential role in treating ALI15. Particularly, Treg contributes to the resolution of fibroproliferation in ALI8. However, a recent study showed that an increased ratio of Tregs is an independent risk factor for 30-day mortality in bronchoalveolar lavage fluid (BALF) of patients with ARDS on admission7. In contrast to Tregs, Th17 cell plays a potent proinflammatory role by producing the signature cytokine IL-17A. Th17 cells have been reported to be implicated in autoimmune and lung diseases in animal and clinical studies16,17,18,19,20. Notably, Th17 cells and IL-17 increased in patients with ARDS compared to control group21. Additionally, studies revealed that IL-17A could act as a pro-inflammatory cytokine and may play an important role in ALI induced by lipopolysaccharide or H1N1 influenza virus22,23. Moreover, Bordetella pertussis could promote lung injury by increasing Th17 immunity24. Therefore, CD4+ T-lymphocyte-based therapeutic strategies may be more meaningful in ALI and provide us with a much broader intervention window. Indeed, studies have demonstrated that both losartan and alanylglutamine may protect mice from lipopolysaccharide-induced lung injury by suppressing Th17 immune responses and modulating the Th17/Treg balance in favor of Tregs, respectively11,25. It has been shown that the balance between Th17 and Treg is vital in the development of autoimmune and inflammatory diseases. However, the role of Th17/Treg balance in smoke inhalation-induced acute lung injury is currently unknown. Therefore, the aim of this study was to investigate the Th17/Treg pattern in rats with gunpowder smog-induced acute lung injury.