Wood JG. Alveolar macrophages are necessary for the systemic inflammation of acute alveolar hypoxia. Alveolar hypoxia (FI O 2 0.10) rapidly produces inflammation in the microcirculation of skeletal muscle, brain, and mesentery of rats. Dissociation between tissue PO2 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

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... nt 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 Ͻ10% of control. Control rats received buffer-containing liposomes. As expected, alveolar hypoxia (FIO 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% O2 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% O2 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. microcirculation; leukocyte-endothelial interactions; reduced inspired oxygen ALVEOLAR HYPOXIA induced by a reduction in inspired PO 2 results in a rapid and widespread inflammatory response in mesentery (7, 37-39) skeletal muscle (9, 28), and brain (23) of rats. This response is characterized by increased leukocyteendothelial interactions (9, 14, 28, 39) , generation of reactive oxygen species (ROS) (14, 37) and depletion of nitric oxide (NO) (31), mast cell activation (9, 32), and increased vascular permeability (14, 38). If hypoxia is maintained for several days, the inflammation subsides and reduction of PO 2 to even lower levels does not elicit inflammation, indicating an Address for reprint requests and other correspondence: N.