ACUTE LUNG INJURY IN ENDOTOXEMIC RATS IS ASSOCIATED WITH SUSTAINED CIRCULATING IL-6 LEVELS AND INTRAPULMONARY CINC ACTIVITY AND NEUTROPHIL RECRUITMENT - ROLE OF CIRCULATING TNF-ALPHA AND IL-BETA

Endotoxemia initiates a cytokine response that is thought to mediate t he syndromes of sepsis and multiple organ failure. This study measured cytokine levels in the blood and airways of rats at critical time poi nts during the development of lung injury induced by chronic endotoxin (LPS) infusion in the rat, Tumor necrosis factor-alpha (TNF), interle ukin-1-beta (IL-l), and interleukin-6 (IL-6) were measured in the bloo d and bronchoalveolar lavage fluid (BALF) of endotoxemic and control a nimals. BALF was also studied for the percentage of neutrophil (PMN) c ount and chemotactic activity. Lung histology was determined at 72 h f ollowing infusion of LPS. Chronic endotoxemia of greater than or equal to 48 h but not less than or equal to 24 h resulted in severe acute l ung injury (ALI). Circulating levels of TNF and IL-l were only transie ntly elevated, whereas IL-6 remained elevated in the endotoxemic rats. TNF, IL-l, and IL-6 levels in BALF were only transiently elevated. Ch emotactic activity, levels of cytokine-induced neutrophil chemoattract ant (CINC), and the percentage of PMN counts in BALF all increased sig nificantly by 36 h. Other potential chemoattractants; leukotriene B-4 and transforming growth factor-beta were not elevated in BALF. In conc lusion, severe ALI requires a minimum of 48 h LPS infusion in this mod el and is associated with high levels of circulating IL-6, increased C INC activity, and an increased percentage of PMN count in BALF. Local inflammatory events may be as important as the systemic cytokine milie u in mediating ALI. The signal for these local events does not appear to depend solely on the transient elevations of circulating TNF and IL -l at the onset of endotoxemia, although sustained high levels of IL-6 may be important.