Roles of IL-1 and TNF in the decreased ileal muscle contractility induced by lipopolysaccharide

Abstract

Gastrointestinal stasis during sepsis may be associated with gastrointestinal smooth muscle dysfunction. Endotoxin [lipopolysaccharide (LPS)] impairs smooth muscle contraction, in part through inducible nitric oxide synthase (NOS II) and enhanced nitric oxide production. We studied the roles of tumor necrosis factor-α (TNF) and interleukin-1 (IL-1) in this process by using TNF binding protein (TNFbp) and IL-1 receptor antagonist (IL-1ra). Rats were treated with TNFbp and IL-1ra, or their vehicles, 1 h before receiving LPS or saline. At 5 h after LPS, contractility was measured in strips of ileal longitudinal smooth muscle, and NOS II activity was measured in full-thickness segments of ileum. LPS decreased maximum stress (mean ± SE) from 508 ± 55 (control) to 355 ± 33 g/cm2( P < 0.05). Pretreatment with TNFbp plus IL-1ra prevented the LPS-induced decrease. Separate studies of TNFbp alone or IL-1ra alone indicated that, at the doses and timing used, TNFbp was more effective. LPS also increased NOS II activity by >10-fold ( P < 0.01) over control. This increase was prevented by TNFbp plus IL-1ra ( P = not significant vs. control). We conclude that the LPS-induced increase in NOS II activity and the decrease in ileal muscle contractility are mediated by TNF and IL-1.

Roles of calcium and IP3 in impaired colon contractility of rats following multiple organ dysfunction syndrome

“…Toxins and cytokines released during sepsis and MODS also unbalance hemodynamic parameters which, in turn, could induce gastrointestinal dysmotility. These factors should be considered when assessing colon motility, but they were not considered in the present study (6,9).…”

“…The cross-sectional area of each strip was calculated from length and weight data by assuming that the density of smooth muscle was 1.05 g/cm 3 . All force development was normalized for tissue cross-sectional area and is reported as stress (9).…”

“…Endotoxin impairs smooth muscle contraction, in part by induction of nitric oxide (NO) synthase and enhanced NO production. Decreased ileal muscle contractility has been reported (9), but colon contractility in MODS animals has not been reported. Therefore, we postulated that colon contractility was weakened during MODS, possibly due to changes in calcium, inositol (1,4,5)-triphosphate (IP 3 ) and NO.…”

“…The increase and fall of intracellular free Ca 2+ initiates contraction and relaxation in smooth muscles (8). Lodato et al (9) reported that gastrointestinal stasis during sepsis may be associated with gastrointestinal smooth muscle dysfunction. The septic syndrome is a systemic inflammatory response to invading microorganisms.…”

Inducible nitric oxide synthase and tumor necrosis factor-alpha in delayed gastric emptying and gastrointestinal transit induced by lipopolysaccharide in mice

“…Gastric retention and gastrointestinal transit were measured 30 min after ip saline or cytokine injection, or 1 h after sc NOC18 injection. The doses, routes, and time intervals were selected on the basis of previous studies (12)(13)(14)(15), and a preliminary study indicated that these doses were likely to affect gastric emptying, thus precluding insufficient dosing. We limited the time to 30 min in order to measure the injected cytokine (or NO) effect and minimize the effects of other cytokines induced in vivo by injected cytokines (or NO).…”