Inhibition of pulmonary neutrophil trafficking during endotoxemia is dependent on the stimulus for migration

In rat models of Gram-negative pneumonia, pulmonary emigration of neutrophi ls (polymorphonuclear leukocytes [PMNs]) is blocked when rats are made endo toxemic by an intravenous administration of endotoxin (lipopolysaccharide [ LPS]). To test whether dysfunctional PMN migratory responses in the endotox emic rat are specific for airway endotoxin, we gave rats intrapulmonary sti muli known to elicit different adhesion pathways for pulmonary PMN migratio n. Sprague-Dawley rats were treated intravenously with either saline or LPS and then instilled intratracheally with either sterile saline, LPS from Es cherichia coli, interleukin (IL)-1, hydrochloric acid (HCl), zymosan-activa ted serum (ZAS), or lipoteichoic acid (LTA). Three hours later, accumulatio n of PMNs and protein in bronchoalveolar lavage fluid (BALF) were assessed. BALF PMN accumulation in response to intratracheal treatment with LPS (100 %), IL-1 (100%), ZAS (40%), and LTA (58%) was inhibited by endotoxemia. In rats given intratracheal HCl, BALF PMN numbers were unaffected by intraveno us LPS. The pattern of inhibition of migration suggests that intravenous LP S only inhibits migration in response to stimuli for which mi,oration is CD 18-dependent. In contrast to PMN migration, BALE protein accumulation was i nhibited by intravenous LPS only when IL-1 or LPS was used as the intratrac heal stimulus. To characterize further the differential responses to the va rious airway stimuli, the appearance in BALF of tumor necrosis factor-alpha (TNF-alpha) and the PMN chemokine macrophage inflammatory protein (MIP)-2 was measured. Accumulation of PMNs in BALF correlated with the BALF concent rations of MIP-2 (r = 0.846, P < 0.05) and TNF (r = 0.911; P < 0.05). The a bility of intravenous LPS to inhibit pulmonary PMN migration correlated wea kly with MlP-2 (r = 0.659; P < 0.05) and with TNF (r = 0.413; P > 0.05) con centrations in BALF. However, this correlation was strengthened for TNF (r = 0.752; P < 0.05) when data from IL-1-treated animals were excluded. Thus, the presence in BALE of inflammatory mediators that are known to promote C D18-mediated migration correlates with endotoxemia-related inhibition of PM N migration. Furthermore, the pattern of inhibition of pulmonary PMN migrat ion during endotoxemia is consistent with the CD18 requirement of each migr atory stimulus.