The Systemic Inflammation of Alveolar Hypoxia Is Initiated by Alveolar Macrophage-Borne Mediator(s)

Alveolar hypoxia produces widespread systemic inflammation in rats. The inflammation appears to be triggered by activation of mast cells by a mediator released from alveolar macrophages, not by the reduced systemic partial pressure of oxygen (PO2) If this is correct, the following should apply: (1) neither mast cells nor tissue macrophages should be directly activated by hypoxia; and (2) mast cells should be activated when in contact with hypoxic alveolar macrophages, but not with hypoxic tissue macrophages. We sough there to determine whether hypoxia activates isolated alveolar macrophages, peritoneal macrophages, and peritoneal mast cells, and to study the response of the microcirculation to supernatants of these cultures. Rat mesenteric microcirculation intravital microscopy was combined with primary cultures of alveolar macrophages, peritoneal macrophages, and peritoneal mast cells. Supernatant of hypoxic alveolar macrophages, but not of hypoxic peritoneal macrophages, produced inflammation in mesentery. Hypoxia induced a respiratory burst in alveolar, but not peritoneal macrophages. Cultured peritoneal mast cells did not degranulate with hypoxia. Immersion of mast cells in supernatant of hypoxic alveolar macrophages, but not in supernatant of hypoxic peritoneal macrophages, induced mast cell degranulation. Hypoxia induced release of monocyte chemoattractant protein-1, a mast cell secretagogue, from alveolar, but not peritoneal macrophages or mast cells. We conclude that a mediator released by hypoxic alveolar macrophages activates mast cells and triggers systemic inflammation. Reduced systemic PO2 and activation of tissue macrophages do not play a role in this phenomenon. The inflammation could contribute to systemic effects of diseases featuring alveolar hypoxia.