title: Functional heterogeneity of pulmonary surfactant protein-D in cystic fibrosis.
abstract: Pulmonary surfactant protein-D (SP-D) is a soluble collagenous C-type lectin with important anti-microbial and anti-inflammatory properties. Although it is subject to functionally relevant modification by common polymorphisms and unregulated inflammation, the functional status of SP-D in cystic fibrosis (CF) remains unclear. Given the importance of infection and inflammation in CF lung pathology we have undertaken the first systematic analysis of SP-D lectin activity in this population. By ELISA, we found that airway lavage fluid SP-D expression was greater in CF compared to control patients but was reduced in CF patients with infection and correlated negatively with markers of neutrophilic inflammation. In a functional assay, the percentage of SP-D capable of binding zymosan rarely exceeded 60% in CF or control patients and similarly restricted binding activity was observed towards maltose-agarose. SP-D lectin activity also correlated negatively with infection and neutrophilic inflammation but there was little evidence of major proteolytic degradation amongst the non-bound material. SP-D which failed to bind zymosan exhibited features of lower oligomeric form compared to bound material when tested by native gel electrophoresis. Furthermore, when separated by gel chromatography, high and low oligomeric populations of SP-D were observed in CF lavage fluid but only high oligomeric forms exhibited substantial lectin activity towards yeast derived mannan. Our data demonstrate that oligomeric heterogeneity underlies functional diversity amongst SP-D in health and disease and that dynamic regulation of oligomerisation is an important feature of SP-D biology.
authors.affiliation: Department of Child Health, Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Sailesh
authors.initials: S
authors.lastname: Kotecha
authors.forename: Iolo
authors.initials: I
authors.lastname: Doull
authors.forename: Philip
authors.initials: P
authors.lastname: Davies
authors.forename: Zofi
authors.initials: Z
authors.lastname: McKenzie
authors.forename: Jens
authors.initials: J
authors.lastname: Madsen
authors.forename: Howard W
authors.initials: HW
authors.lastname: Clark
authors.forename: Eamon P
authors.initials: EP
authors.lastname: McGreal
mesh_terms: D000293:Adolescent; D001424:Bacterial Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000382:microbiology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002850:Chromatography, Gel; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D008297:Male; D008320:Maltose / Q000378:metabolism; D055503:Protein Multimerization; D037663:Pulmonary Surfactant-Associated Protein D / Q000737:chemistry / Q000378:metabolism*; D012685:Sepharose / Q000378:metabolism; D015054:Zymosan / Q000378:metabolism
chemical_list: D015415:Biomarkers; D037663:Pulmonary Surfactant-Associated Protein D; D008320:Maltose; D015054:Zymosan; D012685:Sepharose
keywords: Cystic fibrosis; Inflammation; Innate immunity; Lectin; Lung; Surfactant protein-D