Alveolar
hypoxia (Fi(O(2)) 0.10) rapidly produces
inflammation in the microcirculation of skeletal muscle, brain, and mesentery of rats. Dissociation between tissue Po(2) values and
inflammation, plus the observation that plasma from hypoxic rats activates mast cells and elicits
inflammation in normoxic tissues, suggest that the response to
hypoxia is initiated when mast cells are activated by an agent released from a distant site and carried by the circulation. These experiments tested the hypothesis that this agent originates in alveolar macrophages (AM). Male rats were depleted of AM by tracheal instillation of
clodronate-containing
liposomes. Four days
after treatment, AM recovered by bronchoalveolar lavage were <10% of control. Control rats received
buffer-containing
liposomes. As expected, alveolar
hypoxia (Fi(O(2)) 0.10) in control rats increased leukocyte-endothelial adherence, produced degranulation of perivascular mast cells, and increased fluorescent
albumin extravasation in the cremaster microcirculation. None of these effects was seen when AM-depleted rats were exposed to
hypoxia. Plasma obtained from control rats after 5 min of breathing 10% O(2) elicited
inflammation when applied to normoxic cremasters. In contrast, normoxic cremasters did not develop
inflammation after application of plasma from hypoxic AM-depleted rats. Supernatant from AM cultured in 10% O(2) produced increased leukocyte-endothelial adherence, vasoconstriction, and
albumin extravasation when applied to normoxic cremasters. Normoxic AM supernatant did not produce any of these responses. The effects of hypoxic supernatant were attenuated by pretreatment of the cremaster with the
mast cell stabilizer cromolyn. These data support the hypothesis that AM are the source of the agent that initiates
hypoxia-induced systemic
inflammation by activating mast cells.