Systemic hypoxia promotes leukocyte-endothelial adherence via reactive oxidant generation

Abstract

We recently demonstrated that systemic hypoxia during reduced inspired PO(2) produces a rapid increase in leukocyte adherence to rat mesenteric venules. Evidence suggests that the mechanism of this response involves decreased nitric oxide (NO) levels. One possible pathway for NO depletion could involve increased reactive oxygen species (ROS) generation resulting in inactivation of NO. The overall goal of the present study was to examine the role of ROS in promoting leukocyte-endothelial adherence during systemic hypoxia. Experiments were designed to 1) evaluate changes in ROS generation in the mesenteric microcirculation during systemic hypoxia, 2) determine how the ROS signal changes when PO(2) levels return to normal after a period of systemic hypoxia, 3) assess the effect of antioxidants on ROS generation during hypoxia, and 4) utilize antioxidants to examine the functional relationship between ROS generation and leukocyte adherence during hypoxia. The major findings from this study are that systemic hypoxia increases ROS generation within the mesenteric microcirculation and that antioxidants prevent the increase in leukocyte-endothelial adhesive interactions observed in hypoxia.

Dissociation between skeletal muscle microvascular Po2and hypoxia-induced microvascular inflammation

“…On the other hand, when cremaster PmO 2 was maintained at 60-70 Torr during SHx (PaO 2 of 35 Ϯ 1 Torr), LEA increased from 2.1 Ϯ 1.1 to 11.1 Ϯ 1.5 leukocytes/100 m (P Ͻ 0.05). The results show a dissociation between PmO 2 and LEA and support the idea that SHx results in the release of a mediator responsible for the inflammatory response.leukocyte-endothelial interactions; cremaster muscle; microcirculation; ischemia; local hypoxia; tissue PO2 SYSTEMIC HYPOXIA RESULTS IN a rapid microvascular inflammatory response characterized by increases in microvascular reactive O 2 species (ROS) (19,20,24) and in venular leukocyte-endothelial adhesive interactions (26). Rats studied after exposure to 4 h of hypoxia in the conscious state show emigration of leukocytes to the perivascular space and elevated vascular permeability (25).…”

“…leukocyte-endothelial interactions; cremaster muscle; microcirculation; ischemia; local hypoxia; tissue PO2 SYSTEMIC HYPOXIA RESULTS IN a rapid microvascular inflammatory response characterized by increases in microvascular reactive O 2 species (ROS) (19,20,24) and in venular leukocyte-endothelial adhesive interactions (26). Rats studied after exposure to 4 h of hypoxia in the conscious state show emigration of leukocytes to the perivascular space and elevated vascular permeability (25).…”

“…Furthermore, leukocyte adherence to the venular endothelium occurs predominantly during reperfusion rather than during ischemia (4,7,8,22,23), whereas in hypoxia this phenomenon occurs when PO 2 is reduced (19,20,24); during normoxic recovery, leukocyte-endothelial adhesive interactions actually subside (19,20,24). Systemic hypoxia in anesthetized rats, however, results in marked arterial hypotension (26).…”

“…Rats studied after exposure to 4 h of hypoxia in the conscious state show emigration of leukocytes to the perivascular space and elevated vascular permeability (25). The inflammatory response to hypoxia has been studied predominantly in the mesenteric microcirculation (19)(20)(21)(24)(25)(26) but has also been observed in venules of the cerebral and cremaster microcirculations (6), indicating that it is a widespread phenomenon. The microvascular lesion eventually resolves; after 3 wk of acclimatization to hypoxia, there is no evidence of leukocyte adherence or emigration in mesentery (26) or cremaster microcirculations (6), and the animals tolerate further reductions in inspired PO 2 without evidence of microvascular inflammation.…”

“…Although the early response to hypoxia has common features with ischemia-reperfusion, their patterns are quite different and demonstrate that hypoxia and ischemia-reperfusion-induced microvascular inflammation are two distinct phenomena: in hypoxia, ROS increase with the reduction in PO 2 and return to normal during normoxic recovery (19)(20)(21)24), whereas in ischemia-reperfusion ROS are low during the ischemic period and increase during reperfusion on reintroduction of O 2 (4,7,8). Furthermore, leukocyte adherence to the venular endothelium occurs predominantly during reperfusion rather than during ischemia (4,7,8,22,23), whereas in hypoxia this phenomenon occurs when PO 2 is reduced (19,20,24); during normoxic recovery, leukocyte-endothelial adhesive interactions actually subside (19,20,24).…”