This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 2008-0417OCv1 41/5/573    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Chao, J. Articles by Gonzalez, N. C. PubMed PubMed Citation Articles by Chao, J. Articles by Gonzalez, N. C.

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

¹ Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas

Correspondence and requests for reprints should be addressed to Norberto C. Gonzalez, M.D., Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd., Mail Stop 3043, Kansas City, KS 66160. E-mail: ngonzale{at}kumc.edu

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 sought here 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.

Key Words: hypoxia • systemic inflammation • alveolar macrophages • mast cells • monocyte chemoattractant protein

CLINICAL RELEVANCE This study demonstrates a direct link, via a circulating mediator, between activation of alveolar macrophages by low alveolar PO2, and degranulation of systemic mast cells, the first step in the systemic inflammatory cascade. A candidate mediator, monocyte chemoattractant protein-1, was identified. Roles of low tissue PO2 and activation of tissue macrophages were ruled out. The phenomenon described could participate in the inflammation underlying the systemic effects seen in conditions associated with low alveolar PO2.