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(American Journal of Pathology. 2006;168:1064-1072.)
© 2006 American Society for Investigative Pathology

Lipoxin A₄ Regulates Bronchial Epithelial Cell Responses to Acid Injury

Caroline Bonnans^*, Koichi Fukunaga^*, Marilyn A. Levy and Bruce D. Levy^*

From the Department of Internal Medicine,^* Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; and the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri

Aspiration of gastric acid commonly injures airway epithelium and, if severe, can lead to respiratory failure from acute respiratory distress syndrome. Recently, we identified cyclooxygenase-2 (COX-2)-derived prostaglandin E₂ (PGE₂) and lipoxin A₄ (LXA₄) as pivotal mediators in vivo for resolution of acid-initiated acute lung injury. To examine protective mechanisms for these mediators in the airway, we developed an in vitro model of acid injury by transiently exposing well-differentiated normal human bronchial epithelial cells to hydrochloric acid. Transmission electron microscopy revealed selective injury to superficial epithelial cells with disruption of cell attachments and cell shedding. The morphological features of injury were substantially resolved within 6 hours. Acid triggered and early marked increases in COX-2 expression and PGE₂ production, and acid-induced PGE₂ significantly increased epithelial LXA₄ receptor (ALX) expression. LXA₄ is generated in vivo during acute lung injury, and we observed that nanomolar quantities increased basal epithelial cell proliferation and potently blocked acid-triggered interleukin-6 release and neutrophil transmigration across well-differentiated normal human bronchial epithelial cells. Expression of recombinant human ALX in A549 airway epithelial cells uncovered ALX-dependent inhibition of cytokine release by LXA₄. Together, these findings indicate that injured bronchial epithelial cells up-regulate ALX in a COX-2-dependent manner to promote LXA₄-mediated resolution of airway inflammation.

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