THE PULMONARY INFLAMMATORY RESPONSE TO EXPERIMENTAL FECAL PERITONITIS- RELATIVE ROLES OF TUMOR-NECROSIS-FACTOR-ALPHA AND ENDOTOXIN

The roles of endotoxin (LPS) and tumor necrosis factor-alpha (TNF-alph a) in the causation of organ injury during sepsis are unclear. To stud y LPS and TNF-alpha: in the genesis of lung inflammation after cecal l igation and puncture (CLP), we used endotoxin-resistant (C3H/HeJ) and endotoxin-sensitive mice (C3H/HeOuJ). We examined lung neutrophil sequ estration, interleukin 1 (IL-1)beta mRNA expression, IL-1 beta protein expression, and injury. We also determined the expression of two C-X- C chemokine mRNAs, macrophage inflammatory protein-2 (MIP-2) and KC, i n the lung to determine whether in vivo, endotoxin, or TNF-alpha are s ignificant modulators of MIP-2 and KC mRNA expression. After CLP, incr eased neutrophils sequestrated in the lungs of both strains of mice an d coincided with an increase in expression of IL-I beta, MIP-2 and KC mRNAs, and IL-1 beta protein. Lung and serum TNF-alpha were significan tly increased in the C3H/HeOuJ strain but not in the C3H/HeJ strain. H istologic studies of the lung revealed similar injury in both strains. Our results suggest that bacterial factors other than endotoxin cause lung neutrophil sequestration and injury after CLP and, further, that TNF-a production is not a prerequisite. Our findings also suggest a p otential role for local pulmonary chemokine production in the control of neutrophil sequestration after CLP.