Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, United States of America.
PLoS One. 2011;6(8):e14829. doi: 10.1371/journal.pone.0014829. Epub 2011 Aug 4.
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.
METHODS/PRINCIPAL FINDINGS: 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.
CONCLUSIONS/SIGNIFICANCE: 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.
在休克状态下，应激肠道释放的损伤性非微生物因素导致急性肺损伤（ALI）和多器官功能障碍综合征（MODS）的发生。由于 Toll 样受体（TLR）作为组织损伤以及微生物入侵的传感器，并且 TLR4 信号在脓毒症和非感染性缺血/再灌注（I/R）损伤模型中均发生，我们假设创伤性失血性休克（T/HS）后肠道肠系膜淋巴中的因素通过 TLR4 激活介导肠源性肺损伤。
方法/主要发现：T/HS 淋巴流出肠道后可重建 ALI 的观点得到了我们的发现的证实，即输注来自全身 T/HS 损伤动物的猪淋巴可诱导野生型（WT）小鼠发生肺损伤。使用携带 TLR4 突变的 C3H/HeJ 小鼠，我们发现 TLR4 激活对于 T/HS 猪淋巴诱导的肺损伤的发展是必要的，这可以通过伊文思蓝染料（EBD）肺通透性和髓过氧化物酶（MPO）水平以及损伤性肺 iNOS 反应的诱导来确定。TRIF 和 Myd88 缺陷完全和部分减弱了 T/HS 淋巴诱导的肺通透性增加。在 TLR2 缺陷小鼠中的进一步研究表明，TLR2 激活不参与 T/HS 淋巴诱导的肺损伤的病理学。最后，淋巴样本中没有细菌、内毒素和细菌 DNA，并且通过内毒素去除柱传递淋巴并不能消除 T/HS 淋巴在未致敏小鼠中引起肺损伤的能力。
结论/意义：我们的研究结果表明，T/HS 后肠道肠系膜淋巴中的非微生物因素能够通过 TLR4 激活重新产生 T/HS 诱导的肺损伤。
