Effect of recombinant human tumor necrosis factor-alpha on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide.

Abstract

Among the important pathophysiologic alterations in the brain in bacterial meningitis are abnormalities of cerebral circulation and metabolism; however, the precise mechanisms by which these disturbances occur are not completely delineated. It has been recently recognized that cytokines are produced by tissues in the central nervous system in meningitis and play a critical role in the host inflammatory response. Because these mediators are involved in circulatory and metabolic disturbances in other tissues in sepsis, we investigated the role of tumor necrosis factor-alpha in the central nervous system in a rabbit model. We found that injection of recombinant human TNF into the cisterna magna in the rabbit led to an acute reduction in cerebral oxygen uptake and a more prolonged reduction in cerebral blood flow. This was accompanied by an increase in intracranial pressure and an increase in cerebrospinal fluid lactate. Reduction in oxygen uptake and increases in intracranial pressure and CSF lactate were blocked by pretreatment with L-NAME, an inhibitor of nitric oxide synthase. Reduction in cerebral blood flow was not affected by L-NAME treatment and was due to increased cerebrovascular resistance and reduced oxygen demand. These results suggest that TNF may be a critical mediator of changes in cerebral circulation and metabolism and that some of these changes occur via the nitric oxide pathway. (J. Clin. Invest. 1995.

Intrauterine inflammation alters cardiopulmonary but not cerebral hemodynamics during open endotracheal tube suction in preterm lambs

“…Experimental and clinical evidence show that the cardiopulmonary and systemic circulations are adversely affected in preterm neonates exposed to intrauterine inflammation (2)(3)(4)(5). This is probably caused by inflammationinduced impairment in pulmonary and systemic vascular development and function (4,(6)(7)(8)(9)(10)(11). Consequently, affected infants are more likely to suffer from inflammation-induced pulmonary hypertension, chronic lung disease, and disrupted cerebral perfusion, resulting in cerebral injury and poor neurological outcome (2,4,5,12,13).…”

TNF-α dilates cerebral arteries via NAD(P)H oxidase-dependent Ca2+ spark activation

“…TNF-␣ has been demonstrated to induce both vasoconstriction and vasodilation by endothelium-dependent and endothelium-independent pathways (4,7,16,22,23,29,32,37,38,44,51). The data reported herein suggest that TNF-␣ activates a dilatory Ca 2ϩ signaling pathway in the smooth muscle cells of small, resistance-sized cerebral arteries.…”

“…TNF-␣ is reported to induce both vasoconstriction and vasodilation. Topical application of TNF-␣ dilated cerebral arterioles (7,37), whereas intracranial injection of TNF-␣ induced cerebrovascular constriction and reduced blood flow (29,38,44). TNF-␣ also dilated mesenteric and cremaster muscle arterioles (4,32,45).…”

“…In bronchial arteries, TNF-␣ initially induced dilation, followed by constriction 2 h later (45). TNF-␣-mediated vasoregulation can also occur through both endothelium-dependent and endothelium-independent mechanisms (4,7,16,22,23,29,32,37,38,44,45,51). Collectively, data suggest that TNF-␣ can induce both vasoconstriction and vasodilation and that its effects may be time dependent.…”

“…However, the regulation of arterial diameter and blood flow by TNF-␣ is complex. Intracranial injection of TNF-␣ in vivo constricted pial arterioles and reduced cerebral blood flow (29,38,44). TNF-␣ also induced procontractile effects in coronary arteries (23,51).…”