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Am. J. Respir. Crit. Care Med., Volume 163, Number 7, June 2001, 1591-1598

Local Inflammatory Responses following Bronchial Endotoxin Instillation in Humans

NAOMI P. O'GRADY, HUGH L. PREAS II, JÉRÔME PUGIN, CARMEN FIUZA, MARGARET TROPEA, DEBRA REDA, STEVEN M. BANKS, and ANTHONY F. SUFFREDINI

Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Medical Critical Care, University Hospital of Geneva, Geneva, Switzerland

To study local lung inflammation, 34 subjects had endotoxin (1-4 ng/kg) instilled into a lung segment and saline instilled into a contralateral segment followed by bronchoalveolar lavage (BAL) at 2 h, 6 h, 24 h, or 48 h. Endotoxin instillation resulted in a focal inflammatory response with a distinct time course. An early phase (2 h to 6 h) revealed an increase in neutrophils (p = 0.0001) with elevated cytokines (tumor necrosis factor [TNF]-alpha , TNF receptors [TNFR], interleukin [IL]-1beta , IL-1 receptor antagonist, IL-6, granulocyte-colony-stimulating factor [G-CSF], all p =< 0.002, but no change in IL-10) and chemokines (IL-8, epithelial neutrophil activating protein-78, monocyte chemotactic protein-1, macrophage inflammatory protein [MIP]-1alpha , MIP-1beta , all p =< 0.001, but no change in growth-regulated peptide-alpha ). A later phase (24 h to 48 h) showed increased neutrophils, macrophages, monocytes, and lymphocytes (all p =< 0.02), and a return to basal levels of most mediators. Elevated levels of inflammatory markers (TNFR1, TNFR2, L-selectin, lactoferrin, and myeloperoxidase) persisted in the BAL at 48 h (p =< 0.001). Increased permeability to albumin occurred throughout both phases (p = 0.001). Blood C-reactive protein, serum amyloid A, IL-6, IL-1ra, G-CSF, but not TNF-alpha increased by 8 h (all p =< 0.008). The local pulmonary inflammatory response to endotoxin has a unique qualitative and temporal profile of inflammation compared with previous reports of intravenous endotoxin challenges. This model provides a means to investigate factors that initiate, amplify, and resolve local lung inflammation.




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