Inflammation
-
A long-lasting antihyperalgesic effect has been demonstrated for intrathecal (IT) clonidine, an alpha2-adrenergic agonist. In the present study, the mechanism and antihyperalgesic effects of IT clonidine were examined post-treatment in a rat model of Complete Freund's Adjuvant (CFA)-induced inflammatory hyperalgesia. Using a chronic model of spinal cord dialysis, we examined the effect of the adjuvant-induced inflammation on spinal release of nitric oxide (NO) and the development of chronic pain and assessed the antinociceptive effects and mechanisms of the alpha2-adrenergic agonist, clonidine (IT). ⋯ CFA injection resulted in significant thermal hyperalgesia throughout the four days of observation. A dose-dependent suppression of thermal hyperalgesia and spinal NO release was observed after IT clonidine treatment. Evidence from this CFA-induced inflammatory pain model suggests that clonidine's spinal antihyperalgesic mechanisms act through inhibition of spinal NO release.
-
Activation of NF-kappaB and production of NF-kappaB-dependent chemokines are thought to be involved in the pathogenesis of neutrophilic lung inflammation. Calpain-1 inhibitor (CI-1) blocks activation of NF-kappaB by preventing proteolysis of the inhibitory protein IkappaB-alpha by the ubiquitin/proteasome pathway. We hypothesized that inhibition of proteasome function with CI-1 would block NF-kappaB activation in vivo after intraperitoneal (i.p.) treatment with bacterial lipopolysaccharide (LPS), and that NF-kappaB inhibition would be associated with suppression of chemokine gene expression and attenuation of neutrophilic alveolitis. ⋯ CI-1 treatment prior to LPS resulted in 40% lower MIP-2 concentration in lung lavage fluid compared to rats treated with vehicle prior to LPS (502 +/- 112 pg/ml vs. 859 +/-144 pg/ml, P < 0.05). In addition, CI-1 treatment substantially inhibited LPS-induced neutrophilic alveolitis (2.7+ /- 1.2 x 10(5) vs. 43.7 +/- 12.2 x 10(5) lung lavage neutrophils, P < 0.01). These data indicate that NF-kappaB inhibition in the liver can alter lung inflammation induced by systemic LPS treatment and suggest that a liver-lung interaction contributes to the inflammatory response of the lung.
-
We have asked whether critically ill cardiac valve surgery patients identified by a high APACHE II score exhibit an increase in the number of proinflammatory CD14+CD16+ monocytes. A group of 12 patients was studied over a period of 5 days post cardiac valve surgery for changes in blood monocyte populations. Patients were selected on day 1 post surgery to either be in good clinical condition (APACHE II Score of < or = 14; N = 9) or to be critically ill (APACHE II score of > or = 24; N = 3). ⋯ By contrast the > or = 24 patients had increased values of these cells with 243 +/- 106 cells per microliter on day 1. The numbers of CD14+CD16+ monocytes returned to the control range over the 5 days of observation in 2 of the > or = 24 patients concomitant with the improvement of the APACHE II score. CD14+CD16+ monocytes remained, however, at a high level in patient #2, the patient with persistently high APACHE II score.
-
Chemokines are important inflammatory mediators that function by activating and recruiting leukocytes to an inflamed tissue. We have recently cDNA cloned the rat chemokine macrophage inflammatory protein-1 alpha (MIP-1 alpha) (1). In the present study, we characterize the biological function of recombinant MIP-1 alpha protein and describe expression of its mRNA both in vitro and in a rat model of lung inflammation. ⋯ The rat alveolar macrophage cell line (NR8383) also showed increased MIP-1 alpha mRNA levels in response to LPS (10 micrograms/ml) with a maximal increase after 6-8 h. The induction of MIP-1 alpha mRNA expression by LPS in NR8383 cells was attenuated by cotreatment with the antioxidants N-acetylcysteine and dimethylsulfoxide, suggesting that the induction of MIP-1 alpha mRNA by LPS is mediated via the generation of reactive oxygen species. We conclude that MIP-1 alpha is a potent chemoattractant for macrophages in vivo, and its mRNA expression in macrophages and BAL cells in response to inflammatory stimuli suggests a fundamental role in acute pulmonary inflammation.
-
The roles of endotoxin (LPS) and tumor necrosis factor-alpha (TNF-alpha) in the causation of organ injury during sepsis are unclear. To study LPS and TNF-alpha in the genesis of lung inflammation after cecal ligation and puncture (CLP), we used endotoxin-resistant (C3H/HeJ) and endotoxin-sensitive mice (C3H/HeOuJ). We examined lung neutrophil sequestration, interleukin 1 (IL-1)beta mRNA expression, IL-1 beta protein expression, and injury. ⋯ Histologic studies of the lung revealed similar injury in both strains. Our results suggest that bacterial factors other than endotoxin cause lung neutrophil sequestration and injury after CLP and, further, that TNF-alpha production is not a prerequisite. Our findings also suggest a potential role for local pulmonary chemokine production in the control of neutrophil sequestration after CLP.