Intravenous injection of trauma-hemorrhagic shock mesenteric lymph causes lung injury that is dependent upon activation of the inducible nitric oxide synthase pathway.
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.
Senthil
Maheswari
M
Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
Watkins
Anthony
A
Barlos
Dimitrios
D
Xu
Da-Zhong
DZ
Lu
Qi
Q
Abungu
Billy
B
Caputo
Frank
F
Feinman
Rena
R
Deitch
Edwin A
EA
D000818:Animals; D004195:Disease Models, Animal; D007275:Injections, Intravenous; D008196:Lymph / Q000502:physiology*; D008297:Male; D008643:Mesentery; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000378:metabolism
D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II