05 Feb

Organ Interactions in the Adult Respiratory Distress Syndrome during Sepsis: Control of Systemic Endotoxemia and Bacteremia

Control of Systemic Endotoxemia and Bacteremia: Role of Hepatic Mononuclear (Kupffer) Cells
Circulating Gram-negative bacterial endotoxin has been extensively implicated in the mediation of early pathogenetic events relevant to sepsis-induced ARDS with multiple systems organ failure. There are a variety of mechanisms, including direct cytotoxic effects of endotoxin on endothelial cells, induction of endothelial cell surface factors that promote neutrophil adherence, activation of phagocytes, “priming” of phagocytes by endotoxin to become hyperactivated in response to other stimuli, and triggering of the complement, kinin, and coagulation protein cascades which synergistically alter endothelial cell metabolic function and structural integrity.

Hepatic mononuclear (reticuloendothelial system) uptake and detoxification of endotoxin is the major mechanism limiting the magnitude and duration of systemic endotoxemia. Although all cells of the reticuloendothelial system, including splenic, pulmonary alveolar, and bone macrophages, have this capacity regardless of location, nearly 90 percent of the body’s reticuloendothelial system mass is contained within the liver, primarily as Kupffer cells lining the sinusoidal vascular network. Furthermore, the efficiency of pulmonary alveolar macrophages to clear infused endotoxin appears limited compared with Kupffer cells, reflecting potential differences in the state of cellular activation and the blood-cell interface in these organs. In addition to clearance of endotoxin by adsorptive endocytosis, phagocytic uptake of microorganisms containing endotoxin, sepsis-related particulates, altered platelets, and products of in-travascular coagulation protects the lungs and ex-trapulmonary organs. Circulating neutrophils function as a complementary “peripheral” clearance system whose dysfunction during granulocytopenia may cause increased levels of circulating endotoxin to surpass hepatic clearance capacity. Therefore, impairment of hepatic reticuloendothelial system phagocytic performance resulting in high-grade systemic endotoxemia and prolonged circulation of the byproducts of sepsis can perpetuate and amplify generalized micro-vascular injury, as indicated in the following tabulation showing potential interactions between the liver and lungs:
1. Impaired Kupffer cell uptake/detoxification of endotoxin, bacteria, and byproducts of sepsis (spillover)
(a) Altered gut-liver axis
(b) Augmented systemic endotoxin generation
(c) Changes in hemodynamic determinants of liver phagocytic clearance
2. Increased postphagocytic release of inflammatory endogenous mediators by endotoxin-activated hepatic macrophages
3. Impaired hepatocyte inflammatory mediator clearance (spillover)
(a) Preexisting hepatic disease
(b) Endotoxin-induced hepatocyte injury
4. Reduced hepatocyte acute-phase protein synthesis and altered intermediary metabolism
5. Altered pulmonary metabolic function in the injured lung
(a) Changes in synthesis/transpulmonary clearance of vasoactive amines and eicosanoids
6. Augmented inflammatory mediator release by endotoxin-activated pulmonary alveolar macrophages in the infected lung

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