Abstract
The extent to which defective innate immune responses contribute to chronic obstructive pulmonary disease (COPD) is not fully understood. Pulmonary surfactant protein A (SP-A) plays an important role in regulating innate immunity in the lungs. In this study, we hypothesised that cigarette smoke (CS) and its component acrolein might influence pulmonary innate immunity by affecting the function of SP-A. Indeed, acrolein-modified SP-A was detected in the lungs of mice exposed to CS for 1 week. To further confirm this finding, recombinant human SP-A (hSP-A) was incubated with CS extract (CSE) or acrolein and then analysed by western blotting and nanoscale liquid chromatography-matrix-assisted laser desorption/ionisation time-of-flight tandem mass spectrometry. These analyses revealed that CSE and acrolein induced hSP-A oligomerisation and that acrolein induced the modification of six residues in hSP-A: His39, His116, Cys155, Lys180, Lys221, and Cys224. These modifications had significant effects on the innate immune functions of hSP-A. CSE- or acrolein-induced modification of hSP-A significantly decreased hSP-A’s ability to inhibit bacterial growth and to enhance macrophage phagocytosis. These findings suggest that CS-induced structural and functional defects in SP-A contribute to the dysfunctional innate immune responses observed in the lung during cigarette smoking.
Highlights
Chronic obstructive pulmonary disease (COPD) describes lung disorders characterised by incompletely reversible airflow obstruction
Because acrolein is endogenously formed through oxidation reactions, to determine whether acrolein in cigarette smoke (CS) directly affects surfactant protein A (SP-A) structure and/or function, we examined the lungs of mice exposed to CS for 1 week
The results of this study suggest that the modification of SP-A by acrolein is one mechanism by which CS may be detrimental to the innate immune response
Summary
Detection of acrolein-modified SP-A in the lungs of CS-exposed mice. Acrolein is present at concentrations of 1–10 μM in the airway secretions and tracheal aspirates of smokers[4], and acrolein adducts are found in bronchoepithelial cells, epithelial and smooth muscle cells of the small vessels and inflammatory cells in the lungs of patients with COPD31. Acrolein adducts were detected by western blotting after 4 h incubating acrolein with and hSP-A (20:1 molar ratio of acrolein to SP-A) (Fig. 2C), there were no significant differences in the CD spectra of hSP-A incubated with vehicle or acrolein for the same time (Supplementary Fig. S2) These results suggested that acrolein modification does not affect the secondary structure of hSP-A. Pre-incubation of hSP-A with 10 μM acrolein, 100 μM acrolein, and CSE decreased the binding ability of hSP-A to S. aureus by 75.4 ± 3.5%, 77.7 ± 5.3%, and 71.9 ± 5.1%, respectively (Fig. 5D) These data indicated that the innate immune activities of SP-A were markedly attenuated by exposure to CSE or acrolein
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