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Mucin Is Produced by Clara Cells in the Proximal Airways of Antigen-Challenged Mice

Departments of Medicine and of Molecular and Cellular Biology, Baylor College of Medicine, Houston; Department of Pulmonary Medicine, M. D. Anderson Cancer Center, Houston; Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas; and Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania

Address correspondence to: Christopher M. Evans, Ph.D., Pulmonary Medicine, M.D. Anderson Cancer Center, 2121 West Holcombe Blvd., Houston, TX 77030. E-mail: cevans{at}mdanderson.org

Airway mucus hypersecretion is a prominent feature of many obstructive lung diseases. We thus determined the ontogeny and exocytic phenotype of mouse airway mucous cells. In naive mice, ciliated ( 40%) and nonciliated ( 60%) epithelial cells line the airways, and > 95% of the nonciliated cells are Clara cells that contain Clara cell secretory protein (CCSP). Mucous cells comprise < 5% of the nonciliated cells. After sensitization and a single aerosol antigen challenge, alcian blue–periodic acid Schiff's positive mucous cell numbers increase dramatically, appearing 6 h after challenge (21% of nonciliated/nonbasal cells), peaking from Days 1–7 (99%), and persisting at Day 28 (65%). Throughout the induction and resolution of mucous metaplasia, ciliated and Clara cell numbers identified immunohistochemically change only slightly. Intracellular mucin content peaks at Day 7, and mucin expression is limited specifically to a Clara cell subset in airway generations 2–4 that continue to express CCSP. Functionally, Clara cells are secretory cells that express the regulated exocytic marker Rab3D and, in antigen-challenged mice, rapidly secrete mucin in response to inhaled ATP in a dose-dependent manner. Thus, Clara cells show great plasticity in structure and secretory products, yet have molecular and functional continuity in their identity as specialized apical secretory cells.

Abbreviations: alcian blue–periodic acid Schiff, AB-PAS • bacterial artificial chromosome, BAC • Clara cell secretory protein, CCSP • cystic fibrosis, CF • chronic obstructive pulmonary disease, COPD • epidermal growth factor, EGF • glutathione S-transferase, GST • horseradish peroxidase, HRP • immunoglobulin, Ig • interleukin, IL • mouse transformed Clara cell, mtCC • periodic acid fluorescent Schiff, PAFS • phosphate-buffered saline, PBS • polymerase chain reaction, PCR • rough endoplasmic reticulum, rER • smooth ER, sER • secretory granule, SG • transmission electron microscopy, TEM • variant CCSP-expressing cells, vCE

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