BackgroundInjurious non-microbial factors released from the stressed gut during shocked states contribute to the development of acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS). Since Toll-like receptors (TLR) act as sensors of tissue injury as well as microbial invasion and TLR4 signaling occurs in both sepsis and noninfectious models of ischemia/reperfusion (I/R) injury, we hypothesized that factors in the intestinal mesenteric lymph after trauma hemorrhagic shock (T/HS) mediate gut-induced lung injury via TLR4 activation.Methods/Principal FindingsThe concept that factors in T/HS lymph exiting the gut recreates ALI is evidenced by our findings that the infusion of porcine lymph, collected from animals subjected to global T/HS injury, into naïve wildtype (WT) mice induced lung injury. Using C3H/HeJ mice that harbor a TLR4 mutation, we found that TLR4 activation was necessary for the development of T/HS porcine lymph-induced lung injury as determined by Evan's blue dye (EBD) lung permeability and myeloperoxidase (MPO) levels as well as the induction of the injurious pulmonary iNOS response. TRIF and Myd88 deficiency fully and partially attenuated T/HS lymph-induced increases in lung permeability respectively. Additional studies in TLR2 deficient mice showed that TLR2 activation was not involved in the pathology of T/HS lymph-induced lung injury. Lastly, the lymph samples were devoid of bacteria, endotoxin and bacterial DNA and passage of lymph through an endotoxin removal column did not abrogate the ability of T/HS lymph to cause lung injury in naïve mice.Conclusions/SignificanceOur findings suggest that non-microbial factors in the intestinal mesenteric lymph after T/HS are capable of recreating T/HS-induced lung injury via TLR4 activation.

The arterial supply to the splanchnic bed comprises three divisions of the abdominal aorta; the coeliac artery; and the superior and inferior mesenteric arteries. • Under physiological conditions, blood flow in the splanchnic circulation is controlled via intrinsic (myogenic and metabolic) and extrinsic (autonomic and humoral) mechanisms. • The splanchnic bed forms an important circulatory reservoir, which can be mobilized during periods of physiological stress. • Disorders of the splanchnic circulation may contribute to the multi-organ dysfunction syndrome and vice versa. • A number of techniques used in anaesthesia and critical care influence the distribution of blood flow in the splanchnic circulation. The splanchnic circulation is a complex system. A number of important functions depend on its normal operation, including digestion and absorption within the gut, maintenance of the mucosal barrier, and successful healing of surgical anastomoses, but we have little quantitative information about its physiology because routine measurement in humans is so difficult. This article outlines some basic science and describes how influential the splanchnic circulation might be in our clinical practice. Anatomy The term 'splanchnic circulation' describes the blood flow to the abdominal gastrointestinal organs including the stomach, liver, spleen, pancreas, small intestine, and large intestine. It comprises three major branches of the abdominal aorta; the coeliac artery; superior mesenteric artery (SMA); and inferior mesenteric artery (IMA) (Fig. 1). The hepatic portal circulation delivers the majority of the blood flow to the liver. Coeliac artery The coeliac artery is the first major division of the abdominal aorta, branching at T12 in a horizontal direction ∼1.25 cm in length. It shows three main divisions such as the left gastric artery, common hepatic artery, and splenic artery and is the primary blood supply to the stomach, upper duodenum, spleen, and pancreas. Superior mesenteric artery The SMA arises from the abdominal aorta anteriorly at L1, usually 1 cm inferior to the coeliac artery. The five major divisions of the SMA are the inferior pancreaticoduodenal artery, intestinal arteries, ileocolic, right colic, and middle colic arteries. The SMA supplies the lower part of the duodenum, jejunum, ileum, caecum, appendix, ascending colon, and two-thirds of the transverse colon. It is the largest of the splanchnic arterial vessels delivering >10% of the cardiac output and therefore has significant implications for embolic mesenteric ischaemia. Inferior mesenteric artery The IMA branches anteriorly from the abdominal aorta at L3, midway between the renal arteries and the iliac bifurcation. The main branches of the IMA are the left colic artery, the sigmoid branches, and the superior rectal artery. It forms a watershed with the middle colic artery and supplies blood to the final third of the transverse colon, descending colon, and upper rectum. Physiology Resting splanchnic blood flow (SBF) is typically 30 ml min −1 100 ...

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BACKGROUND Trauma/hemorrhagic shock is one of the major consequences of battlefield injury as well as civilian trauma. FTY720 (sphingosine-1 phosphate agonist) has the capability to decrease the activity of the innate and adaptive immune systems and, at the same time, maintain endothelial cell barrier function and vascular homeostasis during stress. For this reason, we hypothesize that FTY720, as part of resuscitation therapy, would limit T/HS induced multiple organ dysfunction syndrome (MODS) in a rodent trauma-hemorrhagic shock (T/HS) model. METHODS Rats subjected to trauma/sham-shock (T/SS) or T/HS (30 mm Hg × 90 min), were administered FTY720 (1 mg/kg) post-T/HS during volume resuscitation. Lung injury (permeability to Evans Blue dye), PMN priming (respiratory burst activity), and RBC rigidity were measured. In addition, lymph duct cannulated rats were used to quantify the effect of FTY720 on gut injury (permeability and morphology) and the biologic activity of T/HS vs. T/SS lymph on PMN-RB and RBC deformability. RESULTS T/HS-induced increased lung permeability, PMN priming and RBC rigidity were all abrogated by FTY720. The systemic protective effect of FTY720 was only partially at the gut level, since FTY720 did not prevent T/HS-induced gut injury (morphology or permeability,) however, it did abrogate T/HS lymph-induced increased respiratory burst and RBC rigidity. CONCLUSION FTY720 limited T/HS-induced MODS (lung injury, red cell injury, and neutrophil priming) as well as T/HS lymph bioactivity, although it did not limit gut injury.