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Clara Cell Secretory Protein Deficiency Alters Clara Cell Secretory Apparatus and the Protein Composition of Airway Lining Fluid

Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Anatomy and Cell Biology, University of Bergen, Bergen, Norway; Department of Human Physiology, Flinders University of South Australia, Adelaide, Australia; and Department of Cell Biology and Anatomy, University of California at Davis, Davis, California

Address correspondence to: Dr. Barry R. Stripp, Department of Environmental and Occupational Health, University of Pittsburgh, FORBL Rm 314, 3343 Forbes Avenue, Pittsburgh, PA 15260. E-mail: brs2{at}pitt.edu

Clara cells represent the predominant secretory cell within distal conducting airways of mammals and exhibit functional alterations with chronic lung disease. We previously demonstrated that Clara cell secretory protein (CCSP) deficiency results in enhanced susceptibility to environmental agents. The present study was undertaken to define changes in Clara cell secretory function associated with CCSP deficiency in knockout mice. Comparative morphometry of Clara cell ultrastructure revealed dramatic alterations in secretory apparatus between wild-type (WT) and CCSP knockout (CCSP-/-) mice. Secretory granules, which occupy greater than 2% of Clara cell cytoplasmic volume in WT mice, were completely absent among Clara cells of CCSP-/- mice. Moreover, Clara cells of CCSP-/- mice exhibited a > 95% reduction in rough endoplasmic reticulum and alterations to Golgi apparatus, relative to WT controls. Ultrastructural perturbations to Clara cells were associated with altered protein composition of airway lining fluid as revealed by two-dimensional gel analysis of bronchoalveolar lavage proteins, but were not associated with altered abundance or secretion of CC26, another Clara cell secretory protein. We conclude that CCSP is required for the appearance of Clara cell secretory granules and that functional changes to Clara cells that result from CCSP deficiency lead to alterations in the composition of epithelial lining fluid.

Abbreviations: Clara cell secretory protein, CCSP • CCSP knockout, CCSP-/- • chromogranin A, CGA • calcitonin gene related peptide, CGRP • chronic obstructive pulmonary disease, COPD • cytochrome P450-2F2, CYP2F2 • rough endoplasmic reticulum, rER • smooth endoplasmic reticulum, sER • wild type, WT

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