Sepsis is characterized by systemic inflammatory response syndrome which often associated with MODS and even death. Besides, the morbidity and mortality rates of sepsis remained stubbornly high despite the progresses in diagnostic approach and supportive treatment[2, 3]. Consequently, it is urgent to discover effective therapeutic targets and intervening measures. Wide arrays of studies confirm that macrophages play an important role in sepsis and other diseases via mediating inflammatory producers[22, 23]. Macrophages can be classified as 2 phenotypes: classically activated (M1) macrophages, contributing to tissue damage by producing excessive reactive cytotoxic oxidants to destroy pathogens, and alternatively activated(M2) macrophages, suppressing inflammation and promoting repair [9, 10]. At the beginning of inflammatory response phase, macrophages are activated by invading pathogens, leading to excessive inflammatory cytokine storm[22, 24]. These inflammatory cytokines without doubt are helpful eliminating pathogens, but these undue productions can be pernicious, leading to a “double-edge sword” property that eliminating pathogens at the expense of organ injury. Based on understanding of molecular mechanisms underlying sepsis, novel therapies have been designed to suppress macrophage induced cytokine storm and transform macrophages from M1 to M2. In in vivo studies, we revealed that interference of IL-6 would alleviate LPS induced inflammatory response. When expression of IL-6 was inhibited, expression of inflammatory cytokines,such as IL-1β and TNF-α༌were significantly decreased, and ratio of M1 macrophage declined while M2 increased.
IL-6 plays vital roles in host defense against acute infections via activating acute-phase reactions and immune responses. In sepsis and other infected lesions, IL-6 is produced by monocytes and macrophages when stimulated with bacterial, viral or fungal components such as lipopolysaccharide and peptidoglycan with PAMPs. IL-6, as a soluble mediator, sends out inflammatory signals from localized lesions to the whole body and provides an SOS signal to trigger the host defense against emergent events such as infection and trauma. Concentration of IL-6 in blood as a prognostic factor has been evaluated in several studies. And results showed that IL-6 has a high sensitivity and specificity for the detection of sepsis or early sepsis[4, 26]. In this study, we constructed sepsis models via Cecal ligation and puncture (CLP), and observed inflammatory response and tissue damage in lung tissue of WT and IL-6 KO mice. Results indicated that when expression of IL-6 were inhibited, expressions of inflammatory cytokines in CLP induced sepsis mice were decreased and the Muridae Sepsis Score were decreased. 24 h after operation, the damage of tissues, particularly the lung, was significantly improved, and the death rate during 48 h after operation was declined in IL-6 KO mice than that of WT. IL-6 is an important inflammatory mediator which plays a crucial role in inducing inflammatory cascade reaction via several signal pathways, including JAK1/STAT3 pathway. When expression of IL-6 was inhibited, CLP induced inflammatory response and organ damage were improved.
Lung tissue is one of the most easily affected organs by sepsis. In sepsis patients, acute lung injury and acute respiratory distress syndrome (ARDS) are the most common and serious complication, the incidence of which is as high as 40% and the mortality is about 40–50%[2, 29]. Sepsis-induced ARDS refers to damage of alveolar epithelial cells and capillary endothelial cells caused by excessive inflammatory cytokines and ROS, which leads to pulmonary edema, diffused interstitial and alveolar damage. The occurrence and development of ARDS are closely associated with pulmonary edema caused by endothelial damage and increased vascular permeability[31, 32]. Integrality of alveolar barrier is essential to prevent pulmonary edema and promote ARDS relief. Therefore, vascular permeability of alveolar epithelium is an important indicator of occurrence and severity of ARDS. In this study, CLP induced sepsis resulted in pulmonary edema, inflammatory cell infiltration and alveolar damage. But in IL-6 KO sepsis mice, above lung injury manifestation was remarkably improved. And lung injury score and wet/dry weight ratio indicated that lung injury especially vascular permeability was mitigated. And when expression of IL-6 was suppressed, infiltration of inflammatory cell, especially M1 macrophage, was decreased CLP induced sepsis mice. Consequently, aforementioned results indicated that when expression of IL-6 was blocked, the inflammatory response of macrophage in CLP induced sepsis was decreased, tissue damage was improved and survival rate of mice was increased.