Trauma Hemorrhagic Shock-Induced Lung Injury Involves a Gut-Lymph-Induced TLR4 Pathway in Mice

Injurious 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.The 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.Our 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

TLR4 deficiency reduces T/HS lymph induced pulmonary iNOS protein levels.

<p>A) and B) Western blot of iNOS in lung WCEs of WT and TLR4^mut mice infused with porcine T/SS and T/HS lymph for 3 hr. B) Densitometry was performed to quantify iNOS and total p42/p44 MAPK expression. Data expressed as mean ± SE (n = 4–7 mice/group).</p

TRIF and Myd88 deficiency confer full and partial protection against T/HS lymph induced microvascular permeability.

<p>A) WT and Myd88^−/− and B) WT and TRIF^mut mice were infused with porcine T/SS and T/HS lymph for 3 hr and lung permeability to EBD was performed. Data expressed as mean ± SE (n = 5–8 mice/ group).</p

TLR2 does not mediate T/HS lymph-induced lung injury.

<p>WT and TLR2^−/− mice infused with porcine T/HS and T/SS lymph for 3 hr. A) Lung permeability to EBD was performed. Data expressed as mean ± SE (n = 4–6 mice/ group). B) MPO levels (U/g) were measured in lung homogenates. Data expressed as mean ± SE (n = 5–6 mice/group).</p

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