Nitric Oxide. III. A molecular prelude to intestinal inflammation.
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Nitric oxide (NO) synthesis is markedly augmented in states of inflammation, largely due to the expression of inducible nitric oxide synthase (iNOS). Although NO has anti-inflammatory consequences under basal conditions, it remains enigmatic as to why NO displays proinflammatory characteristics in chronic inflammation. Either the anti-inflammatory actions are weak and of little consequence or, alternatively, other factors influence the role of NO in chronic inflammation. We propose that the answer to this enigma lies in the conversion of NO to other higher oxides of nitrogen (NO2, nitrogen dioxide; N2O3, dinitrogen trioxide; and ONOO-, peroxynitrite). Emerging therapeutic strategies may be independent of NO synthesis; e.g., antioxidants have no direct interaction with NO but attenuate the levels and activity of higher nitrogen oxides. Thus, whereas iNOS may be a marker for the proinflammatory actions of NO, the species that mediate tissue injury/dysfunction in inflammation are likely to be nitrogen oxides other than NO. (+info)
Regulation of human airway mucins by acrolein and inflammatory mediators.
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Bronchitis, asthma, and cystic fibrosis, marked by inflammation and mucus hypersecretion, can be caused or exacerbated by airway pathogens or irritants including acrolein, an aldehyde present in tobacco smoke. To determine whether acrolein and inflammatory mediators alter mucin gene expression, steady-state mRNA levels of two airway mucins, MUC5AC and MUC5B, were measured (by RT-PCR) in human lung carcinoma cells (NCI-H292). MUC5AC mRNA levels increased after >/=0.01 nM acrolein, 10 microM prostaglandin E2 or 15-hydroxyeicosatetraenoic acid, 1.0 nM tumor necrosis factor-alpha (TNF-alpha), or 10 nM phorbol 12-myristate 13-acetate (a protein kinase C activator). In contrast, MUC5B mRNA levels, although easily detected, were unaffected by these agonists, suggesting that irritants and associated inflammatory mediators increase mucin biosynthesis by inducing MUC5AC message levels, whereas MUC5B is constitutively expressed. When transcription was inhibited, TNF-alpha exposure increased MUC5AC message half-life compared with control level, suggesting that transcript stabilization is a major mechanism controlling increased MUC5AC message levels. Together, these findings imply that irritants like acrolein can directly and indirectly (via inflammatory mediators) increase airway mucin transcripts in epithelial cells. (+info)
Does a high peritoneal transport rate reflect a state of chronic inflammation?
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OBJECTIVE: It has recently been reported that a high peritoneal transport rate was associated with increased mortality in continuous ambulatory peritoneal dialysis (CAPD) patients. One possible explanation is that a high peritoneal transport rate might be caused by a state of chronic inflammation, which also per se might result in increased mortality. Therefore, in this study we investigated whether high peritoneal transport rate patients are in a state of chronic inflammation. METHODS: The study included 39 clinically stable peritoneal dialysis patients (free of peritonitis) who had been on PD for more than 3 months (16.8+/-11.8 months). Seven patients were treated with continuous cycling peritoneal dialysis (CCPD) and the others were on CAPD. A 4-hour standard peritoneal equilibration test (PET) using 2.27% glucose solution was performed in each patient. Dialysate samples at 4 hours and blood samples at 2 hours were measured for interleukin-1beta (IL-1beta), tumor necrosis factor(alpha)(TNFalpha), C-reactive protein (CRP), and hyaluronan as markers of inflammation. RESULTS: There was no significant correlation between dialysate/plasma (DIP) creatinine (0.82+/-0.15, range 0.51 - 1.15) and blood concentrations of IL-1beta (11.2 ng/L, range <5 - 65.9 ng/L),TNFalpha (12.1 ng/L, range <5 - 85.4 ng/L), CRP (<10 mg/L, range <10 - 76 mg/L), nor with the blood hyaluronan concentration (165 microg/L, range 55 - 955 microg/L). The dialysate concentrations of IL-1beta and TNFalpha were below the detectable level in most of the samples. Although dialysate hyaluronan concentration (334 microg/L, range 89 - 1100 microg/L) was correlated with D/P creatinine (r= 0.36, p< 0.05), there was no correlation between the total amount of hyaluronan in the effluent and D/P creatinine. However, a significant correlation was found between serum hyaluronan concentration and glomerular filtration rate (GFR) (r = -0.49, p< 0.005); GFR also tended to be correlated with serum TNFalpha (r = -0.31, p = 0.058) but not with serum IL-1beta and serum CRP. CONCLUSION: Our results suggest that a high peritoneal transport rate is not necessarily related to a state of chronic inflammation in CAPD patients. The high mortality rate observed in high transporters may relate to other issues, such as fluid balance or abnormal nutrition and metabolism, rather than to chronic inflammation. (+info)
Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma.
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Although matrix metalloproteinases (MMPs) have been reported to play crucial roles in the migration of inflammatory cells through basement membrane components in vitro, the role of MMPs in the in vivo accumulation of the cells to the site of inflammation in bronchial asthma is still obscure. In this study, we investigated the role of MMPs in the pathogenesis of bronchial asthma, using a murine model of allergic asthma. In this model, we observed the increase of the release of MMP-2 and MMP-9 in bronchoalveolar lavage fluids after Ag inhalation in the mice sensitized with OVA, which was accompanied by the infiltration of lymphocytes and eosinophils. Administration of tissue inhibitor of metalloproteinase-2 to airways inhibited the Ag-induced infiltration of lymphocytes and eosinophils to airway wall and lumen, reduced Ag-induced airway hyperresponsiveness, and increased the numbers of eosinophils and lymphocytes in peripheral blood. The inhibition of cellular infiltration to airway lumen was observed also with tissue inhibitor of metalloproteinase-1 and a synthetic matrix metalloproteinase inhibitor. These data suggest that MMPs, especially MMP-2 and MMP-9, are crucial for the infiltration of inflammatory cells and the induction of airway hyperresponsiveness, which are pathophysiologic features of bronchial asthma, and further raise the possibility of the inhibition of MMPs as a therapeutic strategy of bronchial asthma. (+info)
Differential expression and activation of p38 mitogen-activated protein kinase alpha, beta, gamma, and delta in inflammatory cell lineages.
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Four p38 mitogen-activated protein kinases (p38alpha, beta, gamma, delta) have been described. To understand the role of p38 family members in inflammation, we determined their relative expression in cells that participate in the inflammatory process. Expression was measured at the level of mRNA by reverse-transcriptase PCR and protein by Western blot analysis. p38alpha was the dominant form of p38 in monocytes; expression of p38delta was low and p38beta was undetected. In macrophages, p38alpha and p38delta were abundant, but p38beta was undetected. p38alpha and p38delta were also expressed by neutrophils, CD4+ T cells, and endothelial cells. Again, p38beta was not detected in neutrophils, although low amounts were present in CD4+ T cells. In contrast, p38beta was abundant in endothelial cells. p38gamma protein was not detected in any cell type, although p38gamma mRNA was present in endothelial cells. Immunokinase assays showed a strong activation of p38alpha and a lesser activation of p38delta in LPS-stimulated macrophages. Abs specific for mono- and dual-phophorylated forms of p38 suggested that LPS induces dual phosphorylation of p38alpha, but primarily mono-phosphorylation of p38delta. IL-1beta activated p38alpha and p38beta in endothelial cells. However, p38alpha was the more activated form based on kinase assays and phosphorylation analysis. Expression and activation patterns of p38alpha in macrophages and endothelial cells suggest that p38alpha plays a major role in the inflammatory response. Additional studies will be needed to define the contribution of p38delta to macrophage, neutrophil, and T cell functions, and of p38beta to signaling in endothelial cells and T cells. (+info)
A circulating bovine gamma delta T cell subset, which is found in large numbers in the spleen, accumulates inefficiently in an artificial site of inflammation: correlation with lack of expression of E-selectin ligands and L-selectin.
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Tissue-specific localization of TCR-defined subsets of gamma delta T cells has been widely reported; however, the mechanisms responsible for this phenomenon are poorly understood. We describe a bovine gamma delta T cell TCR-associated subset that preferentially localizes in the spleen. This subset was characterized by coexpression of CD8, and was found to lack surface expression of E-selectin ligands, GR Ag ligands, as well as low expression of L-selectin. The CD8-positive gamma delta T cell subset did not accumulate at sites of inflammation as efficiently as CD8-negative gamma delta T cells that, in contrast, express E-selectin and GR ligands and high levels of L-selectin. This is the first demonstration of a gamma delta T cell subset, which exhibits a defined tissue tropism, having a unique adhesion molecule expression profile. These results demonstrate that in some cases tissue-specific accumulation of gamma delta T cell subsets can be predicted by expression, or lack of expression, of defined homing molecules. (+info)
Suppression of airway inflammation by theophylline in adult bronchial asthma.
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BACKGROUND: Chronic continuous airway inflammation caused by eosinophils has been noted to play critical roles in the pathophysiology of bronchial asthma, in addition to reversible obstruction and hypersensitivity of the respiratory tract. Therefore, suppression of chronic airway inflammation has become more important in asthma treatment. Although theophylline has been a conventionally used bronchodilator, it has been recently reported to have concurrent anti-inflammatory effects. OBJECTIVE: Accordingly, we studied the effects of a slow-release theophylline preparation, Theolong, on airway inflammation. METHODS: Administration of Theolong 400 mg/day to 24 patients with mild or moderate asthma and measuring eosinophil cationic protein (ECP), a marker of airway inflammation, and eosinophils in sputum and peripheral blood at 4 and 8 weeks. RESULTS: As a result, sputum ECP, serum ECP and sputum eosinophil count (%) were significantly lowered after 4 and 8 weeks. CONCLUSION: Thus, in the theophylline-administered group, slow-release theophylline, Theolong, was effective in treating asthma, with anti-inflammatory effects on inflammatory cells besides its bronchodilator action. (+info)
Antiproteinuric therapy while preventing the abnormal protein traffic in proximal tubule abrogates protein- and complement-dependent interstitial inflammation in experimental renal disease.
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In proteinuric glomerulopathies, the excess traffic of proteins into the renal tubule is a candidate trigger of interstitial inflammatory and immune events leading to progressive injury, and a key target for the renoprotective action of antiproteinuric drugs. Among proteins trafficked to the proximal tubule, the third component of complement (C3) can be activated locally and contribute to inflammation at sites of protein reabsorption. Experiments were performed in rats with renal mass reduction (RMR, 5/6 nephrectomy) with the following aims: (1) to study Ig (IgG) and complement deposition in proximal tubules, and interstitial macrophage infiltration and MHC class II expression at intervals after surgery by double immunofluorescence analysis; (2) to assess whether lisinopril (angiotensin-converting enzyme inhibitor [ACEi], 25 mg/L in the drinking water, from either day 1 or day 7) limited IgG and C3 accumulation and interstitial inflammation at day 30. In 7-d remnant kidneys, intracellular staining for both IgG and C3 was detectable in proximal tubules in focal areas; C3 was restricted to IgG-positive tubular cells, and there were no interstitial ED-1 macrophage and MHC II-positive cellular infiltrates. In 14-d and 30-d remnant kidneys, proximal tubular IgG and C3 staining was associated with the appearance of interstitial infiltrates that preferentially localized to areas of tubules positive for both proteins. RMR rats given ACEi had no or limited increases in levels of urinary protein excretion, tubular IgG, and C3 reactivity, and interstitial cellular infiltrates in kidneys at 30 d, even when ACEi was started from day 7 after surgery. These findings document that (1) in RMR, IgG and C3 accumulation in proximal tubular cells is followed by leukocyte infiltration and MHC II overexpression in the adjacent interstitium; (2) ACEi while preventing proteinuria limits both tubular accumulation of IgG and C3 and interstitial inflammation. The data suggest that ACE inhibition can be renoprotective by limiting the early abnormal protein traffic in proximal tubule and consequent deleterious effects of excess protein reabsorption, including the accumulation and local activation of complement as well as the induction of chemokines and endothelin genes known to promote interstitial inflammation and fibrosis. (+info)