Abstract
Secretoglobin family 1A member 1 (SCGB 1A1) is a small protein mainly secreted by mucosal epithelial cells of the lungs and uterus. SCGB 1A1, also known as club (Clara) cell secretory protein, represents a major constituent of airway surface fluid. The protein has anti-inflammatory properties, and its concentration is reduced in equine recurrent airway obstruction (RAO) and human asthma. RAO is characterized by reversible airway obstruction, bronchoconstriction and neutrophilic inflammation. Direct effects of SCGB 1A1 on neutrophil functions are unknown. We have recently identified that the SCGB1A1 gene is triplicated in equids and gives rise to two distinct proteins. In this study we produced the endogenously expressed forms of SCGBs (SCGB 1A1 and 1A1A) as recombinant proteins, and analyzed their effects on reactive oxygen species production, phagocytosis, chemotaxis and neutrophil extracellular trap (NET) formation ex vivo. We further evaluated whether NETs are present in vivo in control and inflamed lungs. Our data show that SCGB 1A1A but not SCGB 1A1 increase neutrophil oxidative burst and phagocytosis; and that both proteins markedly reduce neutrophil chemotaxis. SCGB 1A1A reduced chemotaxis significantly more than SCGB 1A1. NET formation was significantly reduced in a time- and concentration-dependent manner by SCGB 1A1 and 1A1A. SCGB mRNA in bronchial biopsies, and protein concentration in bronchoalveolar lavage fluid, was lower in horses with RAO. NETs were present in bronchoalveolar lavage fluid from horses with exacerbated RAO, but not in fluid from horses with RAO in remission or in challenged healthy horses. These findings indicate that SCGB 1A1 and 1A1A have overlapping and diverging functions. Considering disparities in the relative abundance of SCGB 1A1 and 1A1A in airway secretions of animals with RAO suggests that these functional differences may contribute to the pathogenesis of RAO and other neutrophilic inflammatory lung diseases.
Highlights
Secretoglobin family 1A member 1 (SCGB 1A1) is a small, secreted protein mainly produced by mucosal epithelial cells in lung and uterus
SCGB 1A1 and 1A1A inhibit neutrophil extracellular trap (NET) formation ex vivo To determine whether SCGBs affect NETosis, we investigated the kinetics of NET formation in neutrophils treated with different concentrations of recombinant SCGBs by determining fluorescence in plate reader assays and confocal microscopy [29]
SCGB 1A1 is the prototypic member of the secretoglobin family produced by specialized epithelial cells at the mucosal surface of the lungs and uterus
Summary
Secretoglobin family 1A member 1 (SCGB 1A1) is a small, secreted protein mainly produced by mucosal epithelial cells in lung and uterus. SCGB 1A1, known as club (Clara) cell secretory protein (CCSP), was suggested as the standardized nomenclature to define this member of an emerging superfamily of 10 kDa proteins [1]. The SCGB family of proteins exist as disulfide-dependent homodimers that are oriented in an antiparallel superposition [2]. This association generates an internal hydrophobic pocket for binding of lipophilic molecules [3,4,5,6]._ENREF_5 SCGB 1A1 dimers sequester calcium and phosphatidylcholine, a cofactor and a substrate required for phospholipase A2 activity, respectively [7,8]. SCGB 1A1 is highly resistant to protease degradation, and stable at high temperatures and pH extremes [9]
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