No abstract

We investigated in rats the influence of the lymphatic system and of tumor necrosis factor (TNF) on the lung inflammation resulting from intestinal ischemia/reperfusion (I/R) performed by 45-min occlusion of the superior mesenteric artery followed by 2 h of reperfusion. A group of rats had the thoracic lymph duct ligated before I/R. In lungs, intestinal I/R evoked a significant neutrophil recruitment, and enhanced microvascular permeability, in addition to generation of TNF in serum. In the gut, there was lowered lactate dehydrogenase (LDH) activity and increased microvascular permeability. Upon lymph duct ligation, I/R rats had a significant reduction of pulmonary neutrophil recruitment and plasma extravasation, in addition to high amounts of TNF in the lymph, contrasting with undetectable levels in the serum. In addition, LDH gut levels in these animals were close to basal values; there was also some (yet significant) reduction of microvascular permeability, suggesting that the ligation of the lymphatic duct exerted some degree of protection against the intestinal injury caused by I/R. In I/R rats, the treatment with pentoxifylline (PTX) reduced TNF in serum and blunted other lung alterations. The gut alterations caused by intestinal I/R were largely blocked by PTX. On the other hand, in I/R rats with lymph duct ligation, PTX exacerbated the reduction of pulmonary neutrophil recruitment, but did not affect pulmonary and intestinal microvascular permeabilities. Similarly, intestinal LDH activity and serum TNF levels were unaffected. Overall, our data show that the pulmonary and gut injuries induced by intestinal I/R are partially dependent on TNF, which is conceivably generated in the injured gut tissue due to intestinal I/R and carried by the lymphatic system. Thus, the mesenteric lymphatic drainage seems to play a role as a path modulator of the pulmonary and intestinal dysfunctions that follow a gut trauma.

Innate immune responses against microorganisms may be mediated by Toll-like receptors (TLRs). Intestinal ischemia-reperfusion (i-I/R) leads to the translocation of bacteria and/or bacterial products such as endotoxin, which activate TLRs leading to acute intestinal and lung injury and inflammation observed upon gut trauma. Here, we investigated the role of TLR activation by using mice deficient for the common TLR adaptor protein myeloid differentiation factor 88 (MyD88) on local and remote inflammation following intestinal ischemia. Balb/c and MyD88(-/-) mice were subjected to occlusion of the superior mesenteric artery (45 min) followed by intestinal reperfusion (4 h). Acute neutrophil recruitment into the intestinal wall and the lung was significantly diminished in MyD88(-/-) after i-I/R, which was confirmed microscopically. Diminished neutrophil recruitment was accompanied with reduced concentration of TNF-alpha and IL-1beta level. Furthermore, diminished microvascular leak and bacteremia were associated with enhanced survival of MyD88(-/-) mice. However, neither TNF-alpha nor IL-1beta neutralization prevented neutrophil recruitment into the lung but attenuated intestinal inflammation upon i-I/R. In conclusion, our data demonstrate that disruption of the TLR/MyD88 pathway in mice attenuates acute intestinal and lung injury, inflammation, and endothelial damage allowing enhanced survival.

Intestinal I/R (i-I/R) is an insult associated to further adult respiratory distress syndrome and multiple organ failure. This study was designed to evaluate the repercussions of i-I/R on bronchial reactivity to the cholinergic agent methacholine. Anesthetized rats were subjected to superior mesenteric artery occlusion (45 min) and killed after clamp release and defined intestinal reperfusion periods (30 min, 2, 4, or 24 h). Intestinal I/R caused a progressive bronchial hyporesponsiveness (BHR) that was maximal upon 2 h but reverted within 24 h of intestinal reperfusion. The BHR observed at 2-h i-I/R was prevented by NOS inhibitors (N-L-nitroarginine methyl ester and aminoguanidine) or the KATP channel blocker glibenclamide. Moreover, 2-h i-I/R increased the pulmonary iNOS mRNA expression, a fact prevented by lymphatic thoracic duct ligation. The methacholine reactivity of 2-h i-I/R bronchial segments incubated with NOS inhibitors or glibenclamide was similar to that of naive tissues. In vivo blockade of IL-1beta receptors or lymphatic duct ligation before 2-h i-I/R both abolished BHR. Incubation of naive bronchial segments with lymph collected from 2-h i-I/R rats determined BHR, an effect fully preventable by ex vivo blockade of IL-1beta receptors. Incubation of naive bronchial segments with IL-1beta, but not with IL-10 or TNF-alpha, significantly induced BHR that was prevented by N-L-nitroarginine methyl ester. Our data suggest that a gut ischemic insult generates IL-1beta that, upon reperfusion, travels through the lymph into the lungs. In this tissue, IL-1beta would stimulate the generation of NO that orchestrates the ensuing BHR for which the opening of KATP channels seems to play a pivotal role.

Serotonin may contribute to the development and maintenance of remodelling through the release of cytokines and of fibrogenic mediators. Serotonin should therefore be considered as relevant for the development and maintenance of airway remodelling.