Crosstalk between Inflammation and Hemorrhage/Coagulation Disorders in Primary Blast Lung Injury

Abstract

Primary blast lung injury (PBLI), caused by exposure to high-intensity pressure waves from explosions in war, terrorist attacks, industrial production, and life explosions, is associated with pulmonary parenchymal tissue injury and severe ventilation insufficiency. PBLI patients, characterized by diffused intra-alveolar destruction, including hemorrhage and inflammation, might deteriorate into acute respiratory distress syndrome (ARDS) with high mortality. However, due to the absence of guidelines about PBLI, emergency doctors and rescue teams treating PBLI patients rely on experience. The goal of this review is to summarize the mechanisms of PBLI and their cross-linkages, exploring potential diagnostic and therapeutic targets of PBLI. We summarize the pathophysiological performance and pharmacotherapy principles of PBLI. In particular, we emphasize the crosstalk between hemorrhage and inflammation, as well as coagulation, and we propose early control of hemorrhage as the main treatment of PBLI. We also summarize several available therapy methods, including some novel internal hemostatic nanoparticles to prevent the vicious circle of inflammation and coagulation disorders. We hope that this review can provide information about the mechanisms, diagnosis, and treatment of PBLI for all interested investigators.

Keywords: acute lung injury; blast injuries; blood coagulation; hemorrhage; inflammation; therapeutics.

Figure 1

The main pathological manifestations in PBLI. The main pathological manifestations of PBLI are pulmonary hemorrhage, inflammation, and coagulation disorders. The shockwave caused rupture of the pulmonary capillaries, destruction of the alveoli, and entry of red blood cells into the alveolar space and interstitium. Inflammation is manifested by leukocyte infiltration and increased levels of proinflammatory cytokines in the lung. Coagulation disorders are characterized by the aggregation of activated platelets to form platelet thrombi and the gradual formation of fibrin thrombi. NETs: neutrophil extracellular traps.

Figure 2

Hemorrhage promotes inflammation in PBLI. Activated platelets express a variety of cell surface proteins such as CD40Ls, P-selectins, and TLRs to trigger inflammation responses. The p-selectin expressed by activated platelets mediates the binding of platelets to neutrophils. CD40L mediates the binding of platelets to endothelial cells and neutrophils. The expression of TLRs in platelets promotes binding with neutrophils. Upon binding, neutrophils, endothelial cells, and activated platelets initiate an inflammatory response that promotes the release of cytokines. The red blood cells that leak into the alveoli are swallowed by macrophages and release heme and globulin. Heme induces the release of ROS and activation of the NF-κB signaling pathway in macrophages, thereby triggering inflammation. CD40L: cluster of differentiation 40 ligand; NETs: neutrophil extracellular traps; TLR: Toll-like receptor; PI3K: phosphoinositide 3-kinase; NF-κB: nuclear factor kappa B; ROS: reactive oxygen species; IL-1: interleukin-1; IL-8: interleukin-8; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; CCL2: C–C motif chemokine ligand 2; VCAM-1: vascular cell adhesion molecule 1; ICAM-1: intercellular adhesion molecule 1.

Figure 3

Inflammation aggravates coagulation disorders in PBLI. During inflammation, inflammatory factors can promote thrombosis by regulating the coagulation system and fibrinolytic system. (A) Inflammatory factors promote platelet activation and aggregation to form platelet thrombosis. (B) Inflammatory factors cause the downregulation of antithrombin and protein C to inhibit fibrinolysis. (C,D) Inflammatory factors stimulate endothelial cells and monocytes to produce tissue factor, an activator of coagulation, resulting in fibrinous thrombi. (E) Neutrophils are activated by inflammatory factors to produce NETs, which promote coagulation by promoting the production of several coagulation factors. NETs: neutrophil extracellular traps; FXI: coagulation factor XI; FXII: coagulation factor XII.