Hemorrhage alters neuroendocrine, hemodynamic, and compartment-specific TNF responses to LPS.

Abstract

The aim of the present study was to determine the effects of fixed pressure (40 mmHg) hemorrhage (HEM) followed by fluid resuscitation with Ringer's lactate on the subsequent hemodynamic, neurohormonal, and TNF response elicited by systemic lipopolysaccharide (LPS) administration. Chronically catheterized, conscious, unrestrained male Sprague-Dawley rats were randomized to either HEM (n = 12) or sham (n = 12) groups. HEM and sham animals were randomized to receive either LPS (100 mg/100 g body weight) or an equal volume of intravenous saline 1.5 h after completion of the resuscitation period. LPS administration produced an immediate 20% decrease in mean arterial pressure in sham animals, which was accentuated in HEM animals (40%, P < 0.05 versus sham). Moreover, HEM blunted (75%, P < 0.05) the LPS-induced increase in plasma TNF concentrations. TNF was not detected in bronchoalveolar lavage fluid (BALF) obtained from sham LPS-treated animals. In contrast, TNF levels were significantly elevated (35 +/- 17 pg/mL) in HEM LPS-treated animals. A 400% increase in lung TNF content following LPS treatment was not affected by prior HEM. LPS administration produced a marked increase in plasma epinephrine, norepinephrine, and corticosterone levels in sham animals. HEM blunted the LPS-induced rise in circulating levels of epinephrine and corticosterone without altering that of norepinephrine. Our second set of studies showed that the increase in BALF TNF was associated with a 30% increase in wet-to-dry lung weight ratios, suggesting that this is most likely the result of leaky endothelium following hemorrhage and LPS. Furthermore, alterations in LPS-induced alveolar macrophage TNF production following HEM were not detected. These results indicate that HEM altered the hemodynamic, neurohormonal, and circulating TNF responses to systemic LPS administration. In addition, our results suggest that HEM impaired the compartmentalization of the inflammatory response to LPS, without affecting alveolar macrophage responses to LPS. The role of altered neuroendocrine responses to a second challenge in modulating proinflammatory responses remains to be elucidated.