Pulmonary surfactant and neutrophil function in cystic fibrosis

Mander, Ann (1999) Pulmonary surfactant and neutrophil function in cystic fibrosis. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

Pulmonary surfactant is a complex lipid-protein mixture lining the pulmonary epithelium. Although its primary function is to counteract collapsing forces in the alveolic and small airwards during expiration, it also has important immunomodulatory properties. While surfactant lipids suppress various inflammatory cell functions, the hydrophilic surfactant proteins, SP-A and SP-D, enhance the uptake and killing of bacteria by phagocytic cells in the lungs. This thesis was designed to test the central hypothesis that altered surfactant composition may contribute to increased susceptibility to bacterial infections in cystic fibrosis (CF) by adversely affecting the balance between the pro- and anti-inflammatory effects of the surfactant components. The three main aims were: i) to determine the phospholipid (PL) and hydrophilic surfactant protein compositions of bronchoalveolar lavage fluid (BALF) from children with CF, compared to children with a range of respiratory diseases and controls without lung disease, ii) to study the bactericidal functions of neutrophils from CF patients and establish whether they have inherent defects that may contribute to increased susceptibility to lung infections, and iii) to investigate the effects of surfactant components on neutrophil functions in CF, and assess the potential for using surfactant therapeutically to treat lung infections in this disease.

Electrospray ionisation mass spectrometry was employed as a novel method for detailed analyses of PL class and molecular species compositions in small volumes of paediatrics BALF. Although there were no major alterations to surfactant PL compositions, low proportions of the predominant surface active PL, diphalmitoylphosphatidylcholine, were associated with poor lung function in both non-CF and subjects with lung infections. However, in CF, total PL and the proportions of large aggregate material in BALF were both significantly higher than any other subject group. These increases were independent of age or the degree of inflammation in the lungs, and suggested that surfactant PL may accumulate in the lungs of CF patients. By contrast, SP-A was decreased and SP-D profoundly depleted in BALF from CF patients, resulting in severely lowered SP-A/total PL and SP-D/total PL ratios in this disease. The depletion of hydrophilic surfactant proteins appeared to be a secondary effect, associated with increased inflammation in the lung, rather than a primary deficiency in CF.

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