The Association of Circulating Endotoxin with the Development of the Adult Respiratory Distress Syndrome

Abstract

Despite extensive investigation, the pathogenesis of the adult respiratory distress syndrome (ARDS) remains uncertain. As yet, there is no clear explanation of why some patients at risk for ARDS develop the syndrome, whereas others do not. Neutrophils and complement fragments have been implicated in the acute lung injury, but it is clear from published data that evidence of complement activation alone predicts neither the development nor the severity of ARDS. We investigated whether the combination of endotoxin, a leukocyte-priming agent, and complement fragments, leukocyte-stimulating agents, was associated with the development of ARDS. Ninety-eight patients were identified as being either at risk for the development of ARDS or having ARDS, and serial blood samples were obtained. There was no correlation between C5 fragments and the development of ARDS. C3 fragment levels were increased in 89% of the patients with ARDS, but they were also increased in 62% of patients at risk. Endotoxin was detected in 74% of the plasma samples obtained from patients at risk who subsequent developed ARDS and in 64% of the plasma samples obtained from the patients with ARDS. In contrast, only 22% of the plasma samples obtained from the patients at risk who did not develop ARDS had measurable endotoxin. We suggest that the combination of endotoxin and complement fragments may be one mechanism involved in the development of ARDS.

Tumor necrosis factor-alpha inhibits expression of pulmonary surfactant protein.

“…The mechanisms by which infusion of TNFa causes acute lung injury are not completely understood. Activation of complement, induction of a procoagulant endothelial surface, and increased neutrophil production of superoxide anion or secretion oflysomal enzymes have all been observed after TNFa exposure (45). The present work demonstrates a dramatic inhibitory effect of TNFa on surfactant protein expression.…”

A Genomic and Proteomic Analysis of Activation of the Human Neutrophil by Lipopolysaccharide and Its Mediation by p38 Mitogen-activated Protein Kinase

“…1, C and D). Assuming a detection limit for Coomassie of 15 ng (0.25 pmol, or 1.5 ϫ 10 11 molecules, for a 60-kDa protein) and a protein load per gel corresponding to 75 ϫ 10 6 PMNs, we estimate a detection limit on our gels of 2000 molecules/cell for a 60-kDa protein. As investigators have suggested in other cell lines with the use of high resolution two-dimensional-PAGE methods (30), we estimate that Ͼ10,000 proteins are expressed in the resting PMN.…”

“…These "immediate" functional responses, including actin assembly, adhesion, activation of nuclear factor-kappa B (NF-B), and priming for an enhanced secretory response and for release of reactive oxygen intermediates, appear to be central both to the innate immune response and to the pathogenesis of several inflammatory human diseases, including sepsis and the acute respiratory distress syndrome (6). p38 mitogen-activated protein kinase (p38 MAPK) has been shown to mediate LPS-induced PMN adhesion, NF-B activation, and TNF-␣ and IL-8 translation and release (7), and its blockade attenuates LPS-induced PMN accumulation in the airspace (8).…”

Particulate Matter Disrupts Human Lung Endothelial Barrier Integrity via ROS- and p38 MAPK–Dependent Pathways

“…Increased endothelial monolayer permeability is also observed in inflammatory pulmonary conditions, such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis (11), and devastating lung disorders with mortality exceeding 30% (12), as well as more subacute and chronic inflammatory disorders such as asthma.…”