Endotoxin Requirements for Alveolar Macrophage Stimulation

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Abstract
Acute pulmonary failure or ARDS in severely injured patients continues to be a significant problem. The most important clinical risk factor identified is sepsis syndrome. Sepsis syndrome is the clinical correlate of a malignant systemic inflammatory process and is directed in large part by the tissue-fixed macrophage (Mø), such as the alveolar Mø. The Mø is capable of producing most of the central inflammatory mediators responsible for the pathophysiology seen during sepsis and organ injury. Two major mediators are procoagulant activity (PCA), leading to diffuse microvascular thrombosis, and tumor necrosis factor (TNF), causing much of the physiologic derangement of sepsis. Endotoxins (LPS) derived from Gram-negative bacterial cell walls are the primary inflammatory stimulus for the tissue-fixed Mø production of inflammatory mediators. It is not completely known how LPS interacts with its various cellular targets, but it is hoped that knowledge of the molecular interactions involved in stimulation of the Mø by endotoxin will lead to therapies to modulate the responce and prevent deleterious processes suck as ARDS. In the present studies, LPS from E. coli 0111:B4 was shown in a dose response to stimulate large levels of both PCA and TNF in alveolar Mø. LPS from Bacteroides fragilis and Lipid X (the monosaccharide precursor of endotoxin) were unable to cause stimulation of the Mø in vitro. However, both moieties, B. fragilis LPS and Lipid X, were able to effectively and specifically compete with E. coli LPS and block Mø stimulation. Elucidation of the structural differences between E. coli LPS and Lipid X or B. fragilis LPS advances our understanding of the molecular requirements for endotoxin stimulation of the Mø. This provides avenues of study to develop agents that are by themselves non-toxic and non-stimulatory, but capable of blocking the inflammatory response to endotoxin, and thus ameliorate the pathophysiologic response of the host during endotoxemia and sepsis.

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