lipid-a and Lung-Diseases

Three structural features of lipid A (addition of palmitate [C16 fatty acid], addition of aminoarabinose [positively charged amino sugar residue], and retention of 3-hydroxydecanoate [3-OH C10 fatty acid]) were determined for Pseudomonas aeruginosa isolates from patients with cystic fibrosis (CF; n=86), from the environment (n=13), and from patients with other conditions (n=14). Among P. aeruginosa CF isolates, 100% had lipid A with palmitate, 24.6% with aminoarabinose, and 33.3% retained 3-hydroxydecanoate. None of the isolates from the environment or from patients with other conditions displayed these modifications. These results indicate that unique lipid A modifications occur in clinical P. aeruginosa CF isolates.

Topics: Arabinose; Child; Child, Preschool; Chronic Disease; Cystic Fibrosis; Decanoic Acids; Humans; Infant; Lipid A; Lung Diseases; Palmitates; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections

We studied the role of adhesion molecules in acute lung injury caused by lipopolysaccharide (LPS). Forty-eight female guinea pigs were divided into three groups: saline (n = 12); B464, an LPS antagonist, (0.2 mg/kg i.v.) (n = 12); LPS (0.02 mg/kg i.v.) (n = 12); and LPS + B464 (n = 12). The numbers of polymorphonuclear cells (PMN) in blood sampled over 4 hours were counted. Accumulation of PMNs in the lungs was determined by counting the number of PMNs in lung-tissue samples fixed for light-microscopic examination. The lung wet-to-dry weight ratio and the 125I-albumin tissue-to-plasma ratio were used to assess lung injury. Human umbilical-vein endothelial cells were treated with B464 and then stimulated with either LPS or tumor necrosis factor. Expression of ICAM-1 and ELAM-1 was estimated by enzyme-linked immunosorbent assay. After LPS injection, light microscopy revealed decreases in peripheral PMN counts, and accumulation of PMNs in the lungs. Increases in the two indices of lung injury were also observed. These changes were attenuated by prior treatment with B464. The LPS-induced increases in ICAM-1 and ELAM-1 expression were dose-dependently suppressed by B464. These results suggest that pulmonary accumulation of activated PMNs plays an important role in LPS-induced lung injury.

Topics: Acute Disease; Animals; Cells, Cultured; Disease Models, Animal; E-Selectin; Endothelium, Vascular; Female; Guinea Pigs; Humans; Intercellular Adhesion Molecule-1; Lipid A; Lipopolysaccharides; Lung Diseases

We investigated the mechanisms of increase in the pulmonary vascular permeability, focusing on the changes in the peripheral white blood cell (WBC) counts and the surface expression of CD18 on polymorphonuclear cells (PMNs). Anesthetized sheep with chronic lung lymph fistulas were used in this study. We infused synthetic endotoxin (LPS) at a rate of 10 ng/kg/min (i.v.) continuously for 24 hr. We measured lung lymph flow, lymph-to-plasma protein concentration ratio and WBC counts in blood and lung lymph, and the PMNs' surface expression of CD18 before and at 2, 10 and 24 hr after the start of endotoxin infusion, respectively. CD18 was analyzed by flow cytometry using monoclonal anti-CD18 antibody. We found that the pulmonary vascular permeability increased during 2-4 hr after the start of endotoxin infusion, and returned to the baseline over 10 hr. At time 2 hr period, the number of WBCs in the lung lymph increased, the number of peripheral WBCs, mostly PMNs, decreased and the surface expression of CD18 on the peripheral PMNs was up-regulated. At time 10 and 24 hr, the number of WBCs in lung lymph decreased, the number of peripheral WBCs increased and CD18 expression was down-regulated. These data indicate that up-regulation of CD18 expression promotes the PMN adherence to the pulmonary endothelium, migration into the lung and increases the pulmonary vascular permeability. We conclude that the continuous endotoxin infusion up-regulates CD18, which contributes to the PMN migration into the lung.

Topics: Animals; Antigens, Surface; CD18 Antigens; Leukocyte Count; Lipid A; Lung Diseases; Lymphatic System; Neutrophils; Pulmonary Circulation; Sheep

The effects of lipid X and 3-aza-lipid X on in vitro neutrophil function were related to their ability to inhibit the toxicity of endotoxin in galactosamine-sensitized mice. In vitro, lipid X and 3-aza-lipid X (100 ng/ml) blocked completely endotoxin (100 ng/ml)-enhanced neutrophil aggregation, superoxide anion generation, and release of beta-glucuronidase in response to a chemotactic tripeptide, f-met-leu-phe (10(-7) M). In vivo, lipid X at 250 micrograms/mouse (but not 3-aza-lipid X at a similar dose) protected groups of 10 mice from an otherwise lethal dose of endotoxin in galactosamine-sensitized mice when it was administered IV 4 hr or 2 hr before endotoxin challenge. The minimum effective dose of lipid X that could protect 50% of the challenged mice was calculated to be 715 micrograms/kg. However, lipid X failed to suppress neutrophil infiltration into the lungs. The ability of lipid X to inhibit endotoxin-induced neutrophil responses and to protect against lethal endotoxemia may be due to induction of early phase tolerance to endotoxin by the compound.

Topics: Animals; Cell Aggregation; Galactosamine; Glucuronidase; Glycolipids; Humans; In Vitro Techniques; Lipid A; Lipopolysaccharides; Lung Diseases; Male; Mice; Mice, Inbred C57BL; Neutrophils; Shock, Septic; Superoxides