The intratracheal administration of endotoxin: X. Dexamethasone downregulates neutrophil emigration and cytokine expression in vivo.

Intratracheal instillation of endotoxin (LPS) causes acute pulmonary inflammation characterized by the accumulation of plasma proteins and leukocytes within the pulmonary airways. The synthetic glucocorticoid dexamethasone 1) inhibits the LPS-initiated vascular leak of plasma proteins into the airspace, 2) inhibits the LPS-initiated emigration of neutrophils and lymphocytes into the airspace in a dose-dependent fashion, and 3) inhibits LPS-initiated mRNA and/or bronchoalveolar lavage protein expression of cytokines (TNF, IL-1 and IL-6) and chemokines (MIP-1 alpha, MIP-2 and MCP-1). In conclusion, dexamethasone inhibits both the vascular and cellular aspects of acute inflammation by downregulation of a broad spectrum of inflammatory cytokines and chemokines.

Regulation of cytokine gene expression by reactive oxygen and reactive nitrogen intermediates.

Reactive oxygen intermediates (ROI), reactive nitrogen intermediates (RNI), and cytokines are frequent companions at sites of acute inflammation. Previous work has established a clear link between the production of cytokines and the subsequent generation of ROI and RNI. However, more recent data indicates that ROI and RNI not only serve as end-stage effector molecules of pathogen destruction and tissue injury, but also as initiators of acute inflammation.

TNF-alpha potentiates oxidant and reperfusion-induced endothelial cell injury.

Pulmonary edema following reperfusion is a major clinical problem. Changes in endothelial cell shape induced by oxidant injury may account for immediate capillary leakage associated with reperfusion injury. In these experiments we examined the role of tumor necrosis factor-alpha (TNF-alpha) in acute endothelial cell injury following ischemia-reperfusion.

Applied molecular biology of sepsis.

The effective treatment of sepsis and septic shock has remained elusive despite intense research efforts. The tools of molecular biology have been applied to the problem of sepsis in an attempt to design more rational, directed therapy. Cellular interactions with invading microorganisms begin a series of stimulation events within the cell.

Antiserum to tumor necrosis factor and failure to prevent murine colitis.

Cytokines regulate many aspects of disease and have been implicated as mediators of the inflammatory reactions in patients with both ulcerative (UC) and Crohn's colitis. We examined the local and systemic appearance of tumor necrosis factor (TNF) and interleukin 6 (IL-6) in an experimental animal model of inflammatory bowel disease. Colitis was induced in CBA/J mice by adding dextran sulfate sodium (DSS), 5% (wt/vol), to their water.

Cytokines: a primer for plastic surgeons.

Cytokines are peptide mediators of inflammation that are being extensively studied in several aspects of disease. I provide an introduction to the general features of cytokine biology. Cytokines may be considered as either proinflammatory or anti-inflammatory compounds, and they also have potent hematopoietic effects.

Intratracheal injection of endotoxin and cytokines. IX. Contribution of CD11a/ICAM-1 to neutrophil emigration.

Intratracheal injection of endotoxin [lipopolysaccharide (LPS)] in rats causes acute inflammation characterized by the emigration of neutrophils (PMNs) into the bronchoalveolar airspace. Antibody to PMN adhesion molecule CD11a inhibited LPS-initiated PMN accumulation in bronchoalveolar lavage (BAL) fluid by 32% (P < 0.001).

In vivo regulation of replicative Legionella pneumophila lung infection by endogenous tumor necrosis factor alpha and nitric oxide.

The in vivo role of endogenous tumor necrosis factor alpha (TNF-alpha) and reactive nitrogen intermediates (RNIs) in modulation of growth of Legionella pneumophila in the lung was assessed using a murine model of replicative L. pneumophila lung infection. Intratracheal inoculation of mice with L.

Blockade of tumor necrosis factor reduces lipopolysaccharide lethality, but not the lethality of cecal ligation and puncture.

Inhibition of tumor necrosis factor (TNF) bioactivity has afforded protection in several animal models of sepsis. We examined whether inhibition of TNF could improve survival after lethal lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) in CD-1 or BALB/c mice. Neutralizing rabbit anti-TNF antisera were evaluated in CD-1 mice by injecting the antisera 3 h before intravenous (i.

Nitric oxide regulation of IL-8 expression in human endothelial cells.

The regulatory signals required to induce the production of IL-8, an important neutrophil chemoattractant and activator, have yet to be clearly defined. We examined the role of nitric oxide (NO) in IL-8 regulation. The NO synthase inhibitor, (L)-NG-nitroarginine methyl ester (L-NAME), inhibited the TNF-stimulated IL-8 production in the human endothelial cell line, ECV304, in a dose-dependent manner without affecting cellular viability (TNF alone, 5.

Human tumor necrosis factor receptor (p55) and interleukin 10 gene transfer in the mouse reduces mortality to lethal endotoxemia and also attenuates local inflammatory responses.

Anticytokine therapies have been promulgated in gram-negative sepsis as a means of preventing or neutralizing excessive production of proinflammatory cytokines. However, systemic administration of cytokine inhibitors is an inefficient means of targeting excessive production in individual tissue compartments. In the present study, human gene transfer was used to deliver to organs of the reticuloendothelial system antagonists that either inhibit tumor necrosis factor-alpha (TNF-alpha) synthesis or block its interactions with cellular receptors.

Intratracheal administration of endotoxin and cytokines. VI. Antiserum to CINC inhibits acute inflammation.

Cytokine-induced neutrophil chemoattractant (CINC), a chemotactic molecule of the interleukin (IL)-8 family, is known to be induced in the rat in response to tumor necrosis factor (TNF), IL-1, and lipopolysaccharide (LPS). Intratracheal injection of endotoxin (LPS) is shown to cause CINC mRNA expression in pulmonary tissue, peaking after 2 h, and CINC protein expression in bronchoalveolar lavage (BAL) fluid, peaking after 2-4 h. Intratracheal injection of synthetic CINC causes acute inflammation that is abrogated by coinjection of antiserum to purified natural rat CINC.

Regulation of monocyte chemoattractant protein-1 gene expression and secretion in rat pulmonary alveolar macrophages by lipopolysaccharide, tumor necrosis factor-alpha, and interleukin-1 beta.

Chemotactic cytokines coordinate the recruitment of leukocytes into the lung during pulmonary inflammation. In a previous study, we determined that rat pulmonary alveolar macrophages (PAMs) facilitate monocyte recruitment and activation in the lung during acute inflammatory lung injury, in part, through the inducible expression of monocyte chemoattractant protein-1 (MCP-1). MCP-1 is an 11 to 15 kD basic peptide that specifically mediates monocyte chemotaxis and activation.

Monocytes are the major producers of interleukin-1 beta in an ex vivo model of local cytokine production.

Interleukin-1 beta (IL-1 beta) is an early proinflammatory cytokine with multiple effects. Several cells are capable of synthesizing this cytokine, but little is understood about which cell produces IL-1 in disease states. We examined the cellular source of IL-1 in lipopolysaccharide (LPS)-stimulated human whole blood.

Hepatic ischemia/reperfusion injury: importance of oxidant/tumor necrosis factor interactions.

Previous studies have demonstrated a role for both tumor necrosis factor (TNF) and reactive oxygen intermediates (ROI) in hepatic ischemia/reperfusion (I/R) injury. Biologically active TNF was present in liver homogenates in ischemic and nonischemic lobes after 2 h of ischemia but without reperfusion. Using an in situ liver perfusion model, we measured ROI, TNF, and hepatic enzymes in the effluent after 2 h of ischemia.

Intratracheal injection of LPS and cytokines. V. LPS induces expression of LIF and LIF inhibits acute inflammation.

Lipopolysaccharide (LPS) injected into the trachea of rats was found to induce the secretion of leukemia inhibitory factor (LIF) into bronchoalveolar lavage (BAL) fluid with a maximum expression of LIF after 2-12 h. The acute pulmonary neutrophilic inflammation caused by the intratracheal injection of bacterial endotoxin (LPS) could be inhibited by the intratracheal coinjection of recombinant LIF. Compared with intratracheal injection of LPS alone, intratracheal coinjection of LIF and LPS decreases the number of BAL neutrophils obtained 6 h later by approximately 50% (P < 0.

Desferal attenuates TNF release following hepatic ischemia/reperfusion.

Iron chelators have been shown to protect against oxygen free radical injury occurring in association with ischemia/reperfusion (I/R). Tumor necrosis factor alpha (TNF) represents a major mediator of the pulmonary and hepatic injury occurring after hepatic I/R since pretreatment with anti-TNF antibody results in significant protection against both the lung and liver injury following this insult. We were therefore interested in the possible association of the protective actions of deferoxamine (Desferal) following hepatic I/R and subsequent TNF release.

LPS pretreatment protects from hepatic ischemia/reperfusion.

In vivo administration of nonlethal doses of lipopolysaccharide (LPS) to rodents can result in protection from subsequent lethal doses of endotoxin or LPS. We have previously demonstrated that hepatic ischemia/reperfusion (I/R) results in a TNF-dependent lung and liver injury and we postulated that pretreatment with sublethal concentrations of LPS prior to hepatic I/R could be protective from this injury. To test this hypothesis, five groups of rats were studied.

Intratracheal administration of endotoxin and cytokines: VIII. LPS induces E-selectin expression; anti-E-selectin and soluble E-selectin inhibit acute inflammation.

E-selectin is an inducible endothelial adhesion molecule that binds neutrophils. E-selectin mRNA is not constitutively detectable in the lungs of rats. Intratracheal injection of LPS induces pulmonary E-selectin mRNA expression at 2-4 h.

Acute skin injury releases neutrophil chemoattractants.

Background: Progressive or ongoing skin necrosis after traumatic injury is well known. Experimental evidence has associated these events with neutrophil activation and secondary oxidant injury. To determine the mechanism by which neutrophils migrate to a site of injury, cytokine release from injured skin was measured.

Intratracheal administration of endotoxin and cytokines. VII. The soluble interleukin-1 receptor and the soluble tumor necrosis factor receptor II (p80) inhibit acute inflammation.

Intratracheal administration of endotoxin (LPS) causes acute neutrophilic inflammation via induction of pulmonary tumor necrosis factor alpha (TNF) and interleukin-1 (IL-1) expression. In the present study, the anti-inflammatory activity of soluble IL-1 receptor (sIL-1r) and soluble TNF receptor p80 (sTNFr-p80) in LPS-induced acute pulmonary inflammation was investigated. The sIL-1r coinjected intratracheally with LPS in rats significantly inhibits neutrophilic exudation into bronchoalveolar lavage (BAL) fluid by 47% after 6 hr compared to injection of LPS alone.

Production of interleukin-6 and tumour necrosis factor-alpha in vitro is reduced in whole blood of severely malnourished children.

1. Cytokine production in vitro was assessed in 16 malnourished children, before and after nutritional recovery. 2.

Immunological priming attenuates the in vivo pathophysiological response to lipopolysaccharide. Comparison of cytokine production, tissue injury, and lethality in complete Freund's adjuvant-primed mice and in unprimed mice.

Previous reports have indicated that immunological priming of animals will result in increased cytokine production and enhanced susceptibility to the toxicity of cytokines. We primed mice with complete Freund's adjuvant and challenged 2 weeks later with 1 mg/mouse of lipopolysaccharide. Primed mice produced less tumor necrosis factor than naive mice (35 +/- 8 vs 108 +/- 20 ng/ml) and also less interleukin-6 (182 +/- 37 vs 6.