Hemorrhage decreases macrophage inflammatory protein 2 and interleukin-6 release: a possible mechanism for increased wound infection.
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OBJECTIVE: To determine whether alteration in wound exudate cell immune function occurs after trauma-hemorrhage. BACKGROUND: Although clinical and experimental studies indicate that the rate of wound infection is increased after trauma and hemorrhagic shock, the underlying mechanism for this increased susceptibility remains unknown. METHODS: Male C3H/HeN mice were subjected to a midline laparotomy and polyvinyl alcohol sponges were implanted subcutaneously in the abdominal wound before hemorrhage (35+/-5 mm Hg for 90 minutes and resuscitation) or sham operation. The wound exudate cells from the sponges were harvested on the first, third, and fifth postoperative day and cultured for 24 hours in the presence of lipopolysaccharide (10 microg/ml) or heat-killed Staphylococcus aureus. Interleukin (IL)-1beta, IL-6, monocyte chemotactic protein 1, macrophage inflammatory protein 2, and nitrite levels were determined in the supernatants. The distribution of macrophages and polymorphonuclear leukocytes was assessed in the sponge with and without in vivo injection of S. aureus. The phagocytic activity of isolated wound exudate cells was determined using fluorescent S. aureus. RESULTS: The composition of exudate cells was unaltered by hemorrhagic shock; however, in vivo injection of S. aureus significantly decreased the percentage of macrophages under such conditions. Wound exudate cell phagocytic activity and the release of IL-1beta, IL-6, monocyte chemotactic protein 1, and macrophage inflammatory protein 2 was decreased on the first postoperative day. The release of IL-1beta and IL-6 was also decreased on the third postoperative day in hemorrhaged mice. On the fifth postoperative day, wound exudate cell cytokine production was comparable to that in shams. CONCLUSIONS: Because most wound infections occur early after severe trauma, these results suggest that the dysfunction of wound exudate cells after hemorrhage might contribute to the increased incidence of wound infections. Therefore, attempts to enhance or restore wound cell immune function might be helpful for decreasing the incidence of wound infections in trauma victims. (+info)
Synergistic enhancement of chemokine generation and lung injury by C5a or the membrane attack complex of complement.
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Complement plays an important role in many acute inflammatory responses. In the current studies it was demonstrated that, in the presence of either C5a or sublytic forms of the complement-derived membrane attack complex (MAC), rat alveolar macrophages costimulated with IgG immune complexes demonstrated synergistic production of C-X-C (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant) and C-C (macrophage inflammatory protein-1alpha and monocyte chemoattractant-1) chemokines. In the absence of the costimulus, C5a or MAC did not induce chemokine generation. In in vivo studies, C5a and MAC alone caused limited or no intrapulmonary generation of chemokines, but in the presence of a costimulus (IgG immune complexes) C5a and MAC caused synergistic intrapulmonary generation of C-X-C and C-C chemokines but not of tumor necrosis factor alpha. Under these conditions increased neutrophil accumulation occurred, as did lung injury. These observations suggest that C5a and MAC function synergistically with a costimulus to enhance chemokine generation and the intensity of the lung inflammatory response. (+info)
Role of the type 1 TNF receptor in lung inflammation after inhalation of endotoxin or Pseudomonas aeruginosa.
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To determine the roles of the type 1 tumor necrosis factor (TNF) receptor (TNFR1) in lung inflammation and antibacterial defense, we exposed transgenic mice lacking TNFR1 [TNFR1(-/-)] and wild-type control mice to aerosolized lipopolysaccharide or Pseudomonas aeruginosa. After LPS, bronchoalveolar lavage fluid (BALF) from TNFR1(-/-) mice contained fewer neutrophils and less macrophage inflammatory protein-2 than BALF from control mice. TNF-alpha, interleukin-1beta, and total protein levels in BALF as well as tissue intercellular adhesion molecule-1 expression did not differ between the two groups. In contrast, lung inflammation and bacterial clearance after infection were augmented in TNFR1(-/-) mice. BALF from infected TNFR1(-/-) mice contained more neutrophils and TNF-alpha and less interleukin-1beta and macrophage inflammatory protein-2 than that from control mice, but protein levels were similarly elevated in both groups. Lung inflammation and bacterial clearance were also augmented in mice lacking both TNF receptors. Thus TNFR1 facilitates neutrophil recruitment after inhalation of lipopolysaccharide, in part by augmenting chemokine induction. In contrast, TNFR1 attenuates lung inflammation in response to live bacteria but does not contribute to increased lung permeability and is not required for the elimination of P. aeruginosa. (+info)
Cytokine gene expression after inhalation of corn dust.
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To characterize the time course and localize the production of proinflammatory cytokines after inhalation of corn dust, we exposed mice (C3H/HeBFeJ) by inhalation challenge to sterile corn dust extract (CDE) and contrasted this response to inhalation of Escherichia coli 0111:B4 lipopolysaccharide (LPS) or pyrogen-free saline. After both CDE and LPS exposure, an increase in the concentration of bronchoalveolar lavage neutrophils was detected 1 h postinhalation and persisted for 48 h. Significant increases in the bronchoalveolar lavage concentration of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, and macrophage inflammatory protein (MIP)-2 resulted after inhalation of either CDE or LPS. Although the time courses of these cytokines were distinct, a similar pattern of release was observed after both CDE and LPS exposure. A single inhalation exposure of either CDE or LPS resulted in enhanced expression of mRNA for TNF-alpha, IL-1alpha, and MIP-2 that was evident and most pronounced within 1 h of the inhalation challenge. Although enhanced expression of mRNA for TNF-alpha was detectable 12 h after completion of the inhalation challenge, IL-1alpha and MIP-2 mRNA expression remained elevated through the 24-h time point. TNF-alpha, IL-1alpha, and MIP-2 expression was localized by in situ hybridization to inflammatory cells in the airways and alveoli from 1 to 24 h in both CDE- and LPS-exposed lungs. Interestingly, there was no convincing evidence that MIP-2 was substantially produced by airway epithelial cells. The pattern, timing, and location of expression of TNF-alpha, IL-1alpha, and MIP-2 mRNA after a single inhalation exposure of CDE in comparison with LPS is similar, supporting a common etiology and mechanism of inflammation in the lower respiratory tract. Moreover, our findings indicate that inhalation of corn dust or LPS results in an acute inflammatory process that is primarily mediated by inflammatory cells and appears to be self-limited. (+info)
Involvement of p38 MAPK and ERK/MAPK pathways in staurosporine-induced production of macrophage inflammatory protein-2 in rat peritoneal neutrophils.
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Stimulation of rat peritoneal neutrophils with staurosporine (64 nM) induced production of macrophage inflammatory protein-2 (MIP-2) and phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase/MAP kinase (ERK/MAPK). The staurosporine-induced MIP-2 production at 4 h was inhibited by the highly specific p38 MAPK inhibitor SB 203580 and the MAPK/ERK kinase (MEK-1) inhibitor PD 98059 in a concentration-dependent manner. By treatment with SB 203580 (1 microM) or PD 98059 (50 microM), the staurosporine-induced increase in the levels of mRNA for MIP-2 was only partially lowered, although the staurosporine-induced MIP-2 production was completely inhibited. Consistent with the inhibition by the protein synthesis inhibitor cycloheximide, SB 203580 and PD 98059 inhibited MIP-2 production at 4 h either when added simultaneously with staurosporine or 2 h after stimulation with staurosporine. In contrast, the DNA-dependent RNA polymerase inhibitor actinomycin D did not inhibit MIP-2 production at 4 h when it was added 2 h after staurosporine stimulation. Dot blot analysis demonstrated that treatment with SB 203580 or PD 98059 down-regulates the stability of MIP-2 mRNA. These results suggested that p38 MAPK and ERK/MAPK pathways are involved in translation of MIP-2 mRNA to protein and stabilization of MIP-2 mRNA. (+info)
Mycoplasmal lipopeptide MALP-2 induces the chemoattractant proteins macrophage inflammatory protein 1alpha (MIP-1alpha), monocyte chemoattractant protein 1, and MIP-2 and promotes leukocyte infiltration in mice.
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Natural as well as experimental infections with pathogenic mycoplasmas lead to cellular responses characterized by early polymorphonuclear leukocyte influx, which in turn is followed by infiltration of macrophages. Since some of the most potent leukocyte chemoattractants are macrophage products, we investigated whether the 2-kDa macrophage-activating lipopeptide (MALP-2) from Mycoplasma fermentans was capable of inducing chemoattractant chemokines and initiating an in vivo inflammatory effect. MALP-2 was a potent in vitro inducer of the chemokines macrophage inflammatory protein 1alpha (MIP-1alpha), monocyte chemoattractant protein 1 (MCP-1), and MIP-2, yielding a maximal response at 0.1 ng/ml (5 x 10(-11) M). Leukocyte infiltration was determined after intraperitoneal injection of MALP-2, liposome-encapsulated MALP-2, and heat-killed mycoplasmas. There was a steady increase in the number of peritoneal cells over 72 h in response to these agents. Polymorph counts were maximal by 24 to 48 h, decreasing thereafter. Monocytes/macrophages had significantly increased after 3 days. MIP-1alpha, MCP-1, and MIP-2 levels in serum or peritoneal lavage fluid were determined. MIP-1alpha and MCP-1 levels were elevated by 2 to 6 h after injection and were still above control values after 24 h. In contrast, MIP-2 levels reached their maximum at 2 h, dropping to control values after 24 h. We conclude that macrophage-stimulating mycoplasmal lipoproteins, exemplified by MALP-2, play an important role in the late phase of phagocyte recruitment at sites of infection and that this is affected by leukoattractive chemokines. (+info)
Lipoxin (LX)A4 and aspirin-triggered 15-epi-LXA4 inhibit tumor necrosis factor 1alpha-initiated neutrophil responses and trafficking: regulators of a cytokine-chemokine axis.
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The impact of lipoxin A4 (LXA4) and aspirin-triggered lipoxins (ATLs) was investigated in tumor necrosis factor (TNF)-alpha-initiated neutrophil (polymorphonuclear leukocyte) responses in vitro and in vivo using metabolically stable LX analogues. At concentrations as low as 1-10 nM, the LXA4 and ATL analogues each inhibited TNF-alpha-stimulated superoxide anion generation and IL-1beta release by human polymorphonuclear leukocytes. These LXA4-ATL actions were time and concentration dependent and proved selective for TNF-alpha, as these responses were not altered with either GM-CSF- or zymosan-stimulated cells. TNF-alpha-induced IL-1beta gene expression was also regulated by both anti-LXA4 receptor antibodies and LXA4-ATL analogues. In murine air pouches, 15R/S-methyl-LXA4 dramatically inhibited TNF-alpha-stimulated leukocyte trafficking, as well as the appearance of both macrophage inflammatory peptide 2 and IL-1beta, while concomitantly stimulating IL-4 in pouch exudates. Together, these results indicate that both LXA4 and ATL regulate TNF-alpha-directed neutrophil actions in vitro and in vivo and stimulate IL-4 in exudates, playing a pivotal role in immune responses. (+info)
Mechanisms of lung neutrophil activation after hemorrhage or endotoxemia: roles of reactive oxygen intermediates, NF-kappa B, and cyclic AMP response element binding protein.
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Acute inflammatory lung injury occurs frequently in the setting of severe infection or blood loss. Accumulation of activated neutrophils in the lungs and increased pulmonary proinflammatory cytokine levels are major characteristics of acute lung injury. In the present experiments, we examined mechanisms leading to neutrophil accumulation and activation in the lungs after endotoxemia or hemorrhage. Levels of IL-1 beta, TNF-alpha, and macrophage inflammatory protein-2 mRNA were increased in lung neutrophils from endotoxemic or hemorrhaged mice compared with those present in lung neutrophils from control mice or in peripheral blood neutrophils from endotoxemic, hemorrhaged, or control mice. The transcriptional regulatory factors NF-kappa B and cAMP response element binding protein were activated in lung but not blood neutrophils after hemorrhage or endotoxemia. Xanthine oxidase inhibition, achieved by feeding allopurinol or tungsten-containing diets, did not affect neutrophil trafficking to the lungs after hemorrhage or endotoxemia. Xanthine oxidase inhibition did prevent hemorrhage- but not endotoxemia-induced increases in proinflammatory cytokine expression among lung neutrophils. Hemorrhage- or endotoxemia-associated activation of NF-kappa B in lung neutrophils was not affected by inhibition of xanthine oxidase. cAMP response element binding protein activation was increased after hemorrhage, but not endotoxemia, in mice fed xanthine oxidase-inhibiting diets. Our results indicate that xanthine oxidase modulates cAMP response element binding protein activation and proinflammatory cytokine expression in lung neutrophils after hemorrhage, but not endotoxemia. These findings suggest that the mechanisms leading to acute inflammatory lung injury after hemorrhage differ from those associated with endotoxemia. (+info)