Pulmonary host defense employs a combination of biochemical and biophysical activities to recognize, inactivate, and mediate clearance of environmental agents as well as modulate the overall response to such challenge. Dysregulation of the inflammatory arm of this response is associated with chronic lung diseases (CLD) including cystic fibrosis and chronic obstructive lung disease. Although mechanisms mediating immunoregulation are incompletely characterized, decrements in levels of the nonciliated secretory cell product Clara cell secretory protein (CCSP) in numerous CLD and identification of pro-inflammatory state in mice homozygous for a null allele of the CCSP gene (CCSP-/-) suggest a central role for the nonciliated secretory cell in this process. In an effort to determine the molecular basis for immunoregulatory defects associated with CCSP deficiency, we utilized difference gel electrophoresis in combination with MALDI-TOF to compare the proteomes of wild type and CCSP-/- mice. We demonstrate a shift in the pI of the immunomodulatory protein Annexin A1 (ANXA1) to more acidic isoforms in CCSP-/- mice. Similar ANXA1 mRNA and protein abundance in wild type and CCSP-/- tissue and identical localization of ANXA1 protein to alveolar macrophages and the ciliary bed of ciliated cells demonstrated that CCSP deficiency was associated exclusively with altered post-translational modification of ANXA1. These results suggest that both long and short range paracrine signaling between nonciliated secretory cells and cells of the immune system and epithelium impact modification of cell type specific proteins and implicate nonciliated secretory cells in a regulatory axis that might integrate critical aspects of host defense.