Activation of Toll-Like Receptor 4 Is Necessary for Trauma Hemorrhagic Shock-Induced Gut Injury and Polymorphonuclear Neutrophil Priming

Abstract

Interactions of Toll-like receptors (TLR) with non-microbial factors plays a major role in the pathogenesis of early trauma-hemorrhagic shock (T/HS)-induced organ injury and inflammation. Thus, we tested the hypothesis that TLR4 mutant (TLR4mut) mice would be more resistant to T/HS-induced gut injury and neutrophil (PMN) priming than their wild-type (WT) littermates and found that both were significantly reduced in the TLR4mut mice. Additionally, the in vivo and ex vivo PMN priming effect of T/HS intestinal lymph observed in the WT mice was abrogated in TLR4mut mice as well the TRIFmut deficient mice and partially attenuated in Myd88-/- mice suggesting that TRIF activation played a more predominant role than MyD88 in T/HS lymph-induced PMN priming. PMN depletion studies showed that T/HS lymph-induced acute lung injury (ALI) was PMN-dependent, since lung injury was totally abrogated in PMN-depleted animals. Since the lymph samples were sterile and devoid of endotoxin or bacterial DNA, we investigated whether the effects of T/HS lymph was related to endogenous non-microbial TLR4 ligands. HMGB1, heat shock protein (Hsp)-70, Hsp27 and hyaluronic acid, since all have been implicated in ischemia-reperfusion-induced tissue injury. None of these ‘danger’ proteins appeared to be involved, since their levels were similar between the sham and shock lymph samples. In conclusion, TLR4 activation is important in T/HS-induced gut injury and in T/HS lymph-induced PMN priming and lung injury. However, the T/HS-associated effects of TLR4 on gut barrier dysfunction can be uncoupled from the T/HS lymph-associated effects of TLR4 on PMN priming.

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

“…LPS introduced into the intraperitoneal cavity enters the systemic circulation via the portal vein and activates the immune system [5], which was confirmed by monitoring serum TNFa in our study. This mimics the clinical situation in cases of severe trauma when the gut barrier is impaired and gram negative bacteria containing LPS enter the blood stream [11,41]. Second, we focused mainly on the cells that have been shown to play an important role in the inflammatory, regenerative, and remodeling phases (1-6 weeks postoperative) of the repair process.…”

Omega-3 polyunsaturated fatty acids inhibit the increase in cytokines and chemotactic factors induced in vitro by lymph fluid from an intestinal ischemia-reperfusion injury model

“…High mobility group box protein 1 (HMGB1) is the endogenous ligand of TLR4 and activated TLR4 may be the most essential trigger for inflammatory responses to I/R injury. NF-kB is the final effector molecule in the TLR4 signaling pathway, and TLR4 activation is important in trauma-hemorrhagic shock (T/HS)-induced gut injury as well as T/HS lymph-induced polymorphonuclear neutrophil priming and lung injury [11].…”

Role of lipase-generated free fatty acids in converting mesenteric lymph from a noncytotoxic to a cytotoxic fluid

“…Studies to date have excluded many of these factors, including bacteria, bacterial products, cytokines, certain danger-associated molecular pattern molecules, activated complement, and others, as being responsible for the cytotoxic activities of T/HS lymph (1,9,32). Thus, while certain unsaturated FFAs have been implicated as major contributors to the endothelial toxicity of T/HS and SMAO lymph, it remains feasible that T/HS lymph contains non-FFA cytotoxic factors.…”

“…It is not surprising that a number of studies have been directed at identifying the exact factors in mesenteric lymph that are responsible for its in vitro and in vivo injury-inducing effects. These studies have ranged from isolation/purification approaches (10,22,33) to proteomics (16,26,29), as well as the direct measurement of putative factors, such as cytokines, bacterial products, and endogenous danger-signaling molecules or alarmins (9,32). This work has documented that a number of likely putative lymph mediators, including endotoxin and cytokines, are not responsible for the physiological activities of shock lymph.…”