Club Cell Secretory Protein in Lung Disease: Emerging Concepts and Potential Therapeutics

Abstract

Club cell secretory protein (CCSP), also known as secretoglobin 1A1 (gene name SCGB1A1), is one of the most abundant proteins in the lung, primarily produced by club cells of the distal airway epithelium. At baseline, CCSP is found in large concentrations in lung fluid specimens and can also be detected in the blood and urine. Obstructive lung diseases are generally associated with reduced CCSP levels, thought to be due to decreased CCSP production or club cell depletion. Conversely, several restrictive lung diseases have been found to have increased CCSP levels both in the lung and in the circulation, likely related to club cell dysregulation as well as increasedlung permeability. Recent studies demonstrate multiple mechanisms by which CCSP dampens acute and chronic lung inflammation. Given these anti-inflammatory effects, CCSP represents a novel potential therapeutic modality in lung disease.

Keywords: CC10; CCSP; SCGB1A1; biomarker; club cell secretory protein; lung biology; secretoglobin 1A1; uteroglobin.

Figure 1

CCSP restrains pulmonary inflammation. CCSP expression is promoted by retinoic acid and glucocorticoids, as well as through the activity of the transcription factor FOXA2. CCSP inhibits acute lung injury by blunting neutrophil lung recruitment through antagonizing VLA-4-mediated endothelial adhesion or inhibiting IL-8-directed chemotaxis. CCSP promotes barrier integrity by reducing the activity of PLA2, an oxidized lipid generator that stimulates epithelial and endothelial permeability. CCSP also controls chronic pulmonary inflammation. CCSP inhibits eosinophilia and Th17 responses mediated by osteopontin expression and antigen presentation. Furthermore, CCSP inhibits Th2 cytokine expression, which in turn antagonizes FOXA2 expression. Finally, CCSP prevents humoral responses by inhibiting complex formation between IgA and fibronectin. Abbreviations: CCSP, club cell secretory protein; FOXA2, forkhead box A2; IgA, immunoglobulin A; IL-8, interleukin-8; PLA2, phospholipase A2; Th, helper T cell; VLA-4, very late antigen-4.