Malnutrition modifies pig small intestinal inflammatory responses to rotavirus.
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Infectious diarrheal diseases and malnutrition are major causes of child morbidity and mortality. In this study, malnutrition was superimposed on rotavirus infection in neonatal piglets to simulate the combined intestinal stress of viral enteritis in malnourished infants. Two-day-old piglets were assigned to three treatment groups as follows: 1) noninfected, fully nourished; 2) infected, fully nourished; and 3) infected, malnourished. Intestinal indices of inflammation were monitored over the subsequent 2-wk period. Intestinal damage and diarrhea were observed within 2 d of rotavirus infection and began to subside in nourished piglets by d 9 but persisted through d 16 postinfection in malnourished piglets. Rotavirus upregulated small intestinal expression of major histocompatibility complex (MHC) class I and class II genes; malnutrition intensified MHC class I gene expression and suppressed MHC class II expression. Jejunal CD4(+) and CD8(+) T-lymphocyte numbers were elevated for infected, nourished piglets on d 2, 9 and 16 postinfection. Malnutrition did not significantly affect the local expansion of T cell subsets in response to rotavirus. Intestinal prostaglandin E2 (PGE2) concentrations were elevated early after rotavirus infection independent of nutritional state. By d 9, PGE2 concentrations returned to baseline in infected, nourished piglets but remained elevated in malnourished piglets, corresponding to diarrhea observations. Together, the results identify intestinal indices of inflammation that are modulated by malnutrition and prompt reconsideration of current models of rotavirus pathophysiology. (+info)
Inflammation of the brain in Alzheimer's disease: implications for therapy.
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We briefly describe the similarities and differences between a systemic and a local immune reaction and review the evidence that the latter occurs in Alzheimer's disease (AD) brains. The evidence comes mainly from studies on the complement system, microglia, and cytokines, all of which are important actors in the inflammatory process. The evidence is now overwhelming that the complement proteins and many of the mediators of inflammation are produced locally by brain cells. We will mention briefly the many epidemiological studies indicating that the use of anti-inflammatory drugs reduces the incidence and slows the progress of AD. Mention will also be made of some recent work on animal models of possible relevance to AD and inflammation. (+info)
Insights into the neurodegenerative process of Alzheimer's disease: a role for mononuclear phagocyte-associated inflammation and neurotoxicity.
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Since the first description of Alzheimer's disease (AD) in 1907, significant progress was made into understanding disease pathophysiology. The enormous effort in AD research has translated into the discovery of genetic linkages for disease, into elucidating the structure and function of the etiologic beta-amyloid protein, and into unraveling the seemingly complex neuroimmunological cascade that affects neuronal dysfunction. Although effective therapies do not currently exist, many are being developed. We propose that the neuropathogenesis of AD, in measure, revolves around the immunological activation of glial cells, which in turn leads to alterations in inflammatory neurotoxin production, and ultimately to neuronal injury and death. Elucidating the mechanisms involved in such glial cell immune activation should provide valuable insights into understanding the disease process and in providing effective therapeutics to prevent and/or retard the devastating neurodegeneration that afflicts so many of our elderly. (+info)
Interferon response heterogeneity: activation of a pro-inflammatory response by interferon alpha and beta. A possible basis for diverse responses to interferon beta in MS.
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Interferon gamma (IFN-gamma) stimulates the (pro-inflammatory) type II interferon receptor and is known to exacerbate multiple sclerosis (MS). In contrast, IFN-alpha and IFN-beta are ligands for the (anti-inflammatory) type I interferon receptor and are beneficial in some (but not all) patients with MS. Should IFN-beta elicit a type-II-like pro-inflammatory response, the beneficial effects might be attenuated. These studies were undertaken to test this possibility with the use of quinolinic acid (QUIN) formation as a measure of type II receptor activation. In normal human macrophage cultures, IFN-gamma was the most potent stimulus for QUIN formation. Generally, IFN-beta and IFN-alpha were less potent. However, an unexpected inter-patient variability was observed. In some subjects, IFN-alpha was more potent than IFN-beta. In other subjects, IFN-beta was more potent than IFN-alpha. The present data demonstrate an inter-subject variability for QUIN production following exposure to the interferons. MS patients who demonstrate a pro-inflammatory response to IFN-beta (e.g., increased QUIN) may be less likely to benefit from this therapy. (+info)
Macrophage invasion does not contribute to muscle membrane injury during inflammation.
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Previous observations have shown that neutrophil invasion precedes macrophage invasion during muscle inflammation and that peak muscle injury is observed at the peak of ED1+ macrophage invasion. We tested the hypothesis that neutrophil invasion causes subsequent invasion by ED1+ macrophages and that ED1+ macrophages then contribute significantly to muscle membrane injury during modified muscle use. Rat hindlimbs were unloaded for 10 days followed by reloading by normal ambulation to induce inflammation. Membrane injury was measured by assaying Evans blue-bound serum protein influx through membrane lesions. Muscle neutrophil populations increased significantly during the first 2 h of reloading but ED1+ macrophages did not increase until 24 h. Neutrophil invasion was uncoupled from subsequent macrophage invasion by reloading rat hindlimbs for 2 h to cause neutrophil invasion, followed by resuspension for hours 2-24. This produced similar increases in neutrophil concentration as measured in muscles continuously reloaded for 24 h without causing an increase in macrophages. However, resuspension did not reduce the extent of muscle damage compared with that occurring in muscles that were reloaded continuously for 24 h. Thus, muscle invasion by neutrophils is not sufficient to cause invasion by ED1+ macrophages. In addition, muscle membrane injury that occurs during reloading is independent of invasion by ED1+ macrophages. (+info)
Stimulation of the inflammatory system by reamed and unreamed nailing of femoral fractures. An analysis of the second hit.
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It has been suggested that reamed intramedullary nailing of the femur should be avoided in some patients with multiple injuries. We have studied prospectively the effect of femoral reaming on the inflammatory process as implicated in the pathogenesis of acute respiratory distress syndrome (ARDS) and multiple-organ failure (MOF). We studied changes in the levels of serum interleukin-6 (IL-6) (proinflammatory cytokine), neutrophil CD11b (C3) receptor expression (activated neutrophil adhesion molecule), serum soluble intracellular adhesion molecule (s-ICAM-1), serum soluble E-selectin (the soluble products of endothelial adhesion molecules) and plasma elastase (neutrophil protease) in a series of patients with femoral fractures treated by nailing. We have also compared reamed nailing with unreamed nailing. We found that the levels of serum IL-6 and elastase rose significantly during the nailing procedure indicating a measurable 'second hit'. There was no clear response in leukocyte activation and no difference in the release of endothelial adhesion molecule markers. There was no significant difference between groups treated by reamed and unreamed nailing. Although clinically unremarkable, the one patient who died from ARDS was shown to be hyperstimulated after injury and again after nailing, suggesting the importance of an excessive inflammatory reaction in the pathogenesis of these serious problems. Our findings have shown that there is a second hit associated with femoral nailing and suggest that the degree of the inflammatory reaction may be important in the pathogenesis of ARDS and MOF. (+info)
Limited anti-inflammatory efficacy of cyclo-oxygenase-2 inhibition in carrageenan-airpouch inflammation.
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1. Cyclo-oxygenase-2 (COX-2) is expressed at sites of inflammation and is believed to be the major source of inflammation-associated prostaglandin synthesis. Selective inhibition of COX-2 has been suggested to produce anti-inflammatory effects with reduced toxicity in the gastrointestinal tract. We examined the extent to which suppression of COX-2 led to inhibition of various components of inflammation in the carrageenan-airpouch model in the rat. 2. Indomethacin (> or =0.3 mg kg(-1)), nimesulide (> or =3 mg kg(-1)) and the selective COX-2 inhibitor, SC-58125 (> or =0.3 mg kg(-1)), significantly suppressed the production of prostaglandin E2 at the site of inflammation. At higher doses, indomethacin (> or =1 mg kg(-1)) and nimesulide (30 mg kg(-1)), but not SC-58125 (up to 10 mg kg(-1)), significantly inhibited COX-1 activity (as measured by whole blood thromboxane synthesis). 3. All three test drugs significantly reduced the volume of exudate in the airpouch, but only at doses greater than those required for substantial (>90%) suppression of COX-2 activity. Similarly, reduction of leukocyte infiltration was only observed with the doses of indomethacin and nimesulide that caused significant suppression of COX-1 activity. 4. SC-58125 did not significantly affect leukocyte infiltration into the airpouch at any dose tested (up to 10 mg kg(-1)). A second selective COX-2 inhibitor, Dup-697, was also found to suppress exudate PGE2 levels without significant effects on leukocyte infiltration. 5. These results indicate that selective inhibition of COX-2 results in profound suppression of PGE2 synthesis in the carrageenan-airpouch, but does not affect leukocyte infiltration. Exudate volume was only reduced with the highly selective COX-2 inhibitor when a dose far above that necessary for suppression of COX-2 activity was used. Inhibition of leukocyte infiltration was observed with indomethacin and nimesulide, but only at doses that inhibited both COX-1 and COX-2. (+info)
Pro- and anti-inflammatory actions of thrombin: a distinct role for proteinase-activated receptor-1 (PAR1).
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1. Thrombin has well characterized pro-inflammatory actions that have recently been suggested to occur via activation of its receptor, proteinase-activated receptor-1 (PAR1). 2. In the present study, we have compared the effects of thrombin to those of two peptides that selectively activate the PAR1 receptor, in a rat hindpaw oedema model. We have also examined whether or not thrombin can exert anti-inflammatory activity in this model. 3. Both thrombin and the two PAR1 activating peptides induced significant oedema in the rat hindpaw following subplantar injection. 4. The oedema induced by thrombin was abolished by pre-incubation with hirudin, and was markedly reduced in rats in which mast cells were depleted through treatment with compound 48/80 and in rats pretreated with indomethacin. In contrast, administration of the PAR1 activating peptides produced an oedema response that was not reduced by indomethacin and was only slightly reduced in rats pretreated with compound 48/80. 5. Co-administration of thrombin together with a PAR1 activating receptor resulted in a significantly smaller oedema response than that seen with the PAR1 activating peptide alone. This anti-inflammatory effect of thrombin was abolished by pre-incubation with hirudin. 6. These results demonstrate that the pro-inflammatory effects of thrombin occur through a mast-cell dependent mechanism that is, at least in part, independent of activation of the PAR1 receptor. Moreover, thrombin is able to exert anti-inflammatory effects that are also unrelated to the activation of PAR1. (+info)