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Intravenous Injection of Trauma-Hemorrhagic Shock Mesenteric Lymph Causes Lung Injury That Is Dependent Upon Activation of the Inducible Nitric Oxide Synthase Pathway

Senthil, Maheswari MD; Watkins, Anthony MD; Barlos, Dimitrios MD; Xu, Da-Zhong MD, PhD; Lu, Qi MD; Abungu, Billy BSc; Caputo, Frank MD; Feinman, Rena PhD; Deitch, Edwin A. MD

doi: 10.1097/SLA.0b013e3180caa3af
Original Articles

Objective: To test the hypothesis that gut-derived factors carried in trauma-hemorrhagic shock (T/HS) lymph is sufficient to induce lung injury. Additionally, because our previous studies showed that T/HS-induced nitric oxide production was associated with lung injury, we examined whether T/HS lymph-induced lung injury occurs via an inducible nitric oxide synthase (iNOS)-dependent pathway.

Background: We have previously shown that T/HS-induced lung injury is mediated by gut-derived humoral factors carried in the mesenteric lymph. However, it remains unclear whether T/HS lymph itself is sufficient to induce lung injury, or requires the activation of other factors during the T/HS period to exert its effect.

Methods: Mesenteric lymph collected from T/HS or trauma-sham shock (T/SS) animals was injected intravenously into male rats at a rate of 1 mL/h for 3 hours. At the end of infusion, lung injury was assessed by lung permeability and lung histology. The effect of iNOS inhibition on T/HS lymph-induced lung injury was studied and this was further confirmed in iNOS knockout mice. Finally, iNOS immunohistochemistry was performed to identify the cells of origin of iNOS.

Results: The injection of T/HS lymph, but not sham shock lymph, caused lung injury. This was associated with increased plasma nitrite/nitrate levels as well as induction of iNOS protein in the lung, liver, and gut. Treatment with the selective iNOS inhibitor aminoguanidine prevented T/HS lymph-induced lung injury. iNOS knockout mice, but not their wild-type controls, were resistant to T/HS lymph-induced lung injury. By immunohistochemistry, neutrophils and macrophages, rather than parenchymal cells, were the source of T/HS lymph-induced lung iNOS.

Conclusions: These results indicate that T/HS lymph is sufficient to induce acute lung injury and that lymph-induced lung injury occurs via an iNOS-dependent pathway.

This study demonstrates that trauma-hemorrhagic shock mesenteric lymph is sufficient by itself to induce acute lung injury and that lymph-induced lung injury occurs via an inducible nitric oxide synthase-dependent pathway.

From the Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ.

Supported by National Institutes of Health Grant GM059841 (E.A.D.), and T32 GM069330 (F.C.).

Equal contribution by Anthony Watkins and Dimitrios Barlos.

Reprints: Edwin A. Deitch MD, UMDNJ – New Jersey Medical School, Department of Surgery, 185, South Orange Ave., MSB-G 506, Newark, NJ 07103. E-mail:

© 2007 Lippincott Williams & Wilkins, Inc.