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Heinrich, Stefanie May (2011): Human SP-A- genes, structure, function- and lung diseases. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

Surfactant associated protein-A (SP-A) is the most abundant pulmonary surfactant protein and belongs to the family of innate host defence proteins termed collectins. The aim of the study was to elucidate the role of SP-A in human lung disease. This study was designed to analyze the relation between genetics, structure and function of SP-A in a CF, chronic bronchitis and asthma and healthy control population ex vivo. Beginning with the analysis of SP-A oligomeric forms, there were no correlations between serum and BAL SP-A distribution forms. The forms showed only a significantly different distribution comparing serum samples from bronchitis patients and controls. In serum and BAL of CF patients the forms containing the first peak were correlated with a better lung function (Fev1 (% pred.)age20). Also higher relative SP-A amount in the first peak is associated with a milder lung disease and a better course of lung disease. Additionally, SP-A self-agglutination is dependent on the amount of particular SP-A oligomers present in a sample, i.e. the relative strength of SP-A molecular forms in a sample. All SP-A structures self-agglutinate in serum better than in BAL in samples of the patients groups while in control samples BAL and serum SP-A showed the same abilities. There was also a difference between the self-agglutination ability of BAL samples from CF, Bro and control derived SP-A, but none in serum. SP-A from control BAL agglutinated better than from bronchitis BAL and this better than from CF BAL. These results are also supported by the fact that a better agglutination ability of SP-A was significantly associated with lung function. Therefore the degree of the presence of active oligomeric forms within a BAL or serum sample seems to be important for a better lung function outcome. The SP-A oligomerization is associated with one SFTPA1 rs1136451 and one SFTPA2 SNP rs17881665 which are coupled, while the mutated allele seems to cause a lack of complex oligomers. The wildtype alleles of the SP-A2 SNPs rs1965708 and rs1975006 were associated with CF compared to the bronchitis and control group. There was a significant association between the mean ∆ Fev1 (%pred.) / year and V50L a SNP in the SFTPA1 gene (p = 0.0038) while the mutated allele was associated with a worse course of lung disease. The SP-A BAL level was significantly associated with the SP-A1 SNP rs1136451 (p = 0.002) and the SP-A2 SNP rs17881665r (p = 0.002). The SP-A serum level was significantly associated with SP-A1 N9T (p = 0.028). In addition in the CF study population there was a significant association between the SP-A level in BAL and the Fev1 (% pred.) estimated for age 20 (p = 0.009). The higher the SP-A levels were in BAL the bigger were the values of the Fev1 (% pred.) estimated for age 20. There was no correlation between the SP-A BAL or serum level and any other clinical characteristic such as BMI, age, gender, IgG or IgE in serum. In conclusion, these results indicate a very important role for SP-A in human lung immunity. Future areas for clinical research include disease specific SP-A expression pattern and their functional consequences, the differential roles of SP-A1 and SP-A2 in human lung diseases, and therapeutic approaches to correct altered SP-A levels.