Abstract
We have reported that surfactant protein A kills some Gram-negative organisms by increasing membrane permeability. In this study, we investigated the physiologic importance of this activity and the effect of oxidative stress on the antimicrobial functions of SP-A in vitro and in vivo. Concentrated bronchoalveolar lavage fluids from SP-A+/+ mice increased the permeability of the Escherichia coli K12 cell membrane to a greater extent than lavage from SP-A-/- animals. Similarly, calcium-dependent surfactant-binding proteins of SP-A+/+ mice increased membrane permeability more than those from SP-A-/- mice and produced greater zonal killing of agar-embedded bacteria in a radial diffusion assay. Exposure of human SP-A to copper-initiated surfactant phospholipid peroxidation or to free radicals generated by human neutrophils in vitro increased the level of SP-A-associated carbonyl moieties and blocked the permeabilizing function of the protein. We also found that exposure of mice to 90% O2 for 4 days, sufficient to lead to consumption of glutathione, oxidation of protein thiols, and accumulation of airspace protein-associated carbonyl moieties, blocked the permeabilizing activity of lavage fluid from SP-A+/+ mice. We conclude that SP-A is a major microbial permeablizing factor in lavage fluid and that oxidative stress inhibits the antibacterial activity of SP-A by a mechanism that includes oxidative modification and functional inactivation of the protein.
Highlights
Surfactant proteins A and D, known as the pulmonary collectins, play important roles in the innate immune defense of the lung, including the agglutination, opsonization, and augmentation of intraphagocytic killing of a variety of inhaled pathogens [1]
We conclude that SP-A is a major microbial permeablizing factor in lavage fluid and that oxidative stress inhibits the antibacterial activity of SP-A by a mechanism that includes oxidative modification and functional inactivation of the protein
We found that lavage from SP-AϪ/Ϫ mice was much less disruptive to E. coli membranes than lavage from
Summary
Surfactant proteins A and D, known as the pulmonary collectins, play important roles in the innate immune defense of the lung, including the agglutination, opsonization, and augmentation of intraphagocytic killing of a variety of inhaled pathogens [1]. We have recently reported that the pulmonary collectins directly inhibit the growth of microorganisms by induction of membrane permeability [2, 3]. Supplemental oxygen therapy is extensively used in this setting, resulting in conditions that favor formation of reactive oxygen species (ROS) and damage to airway cells and extracellular molecules in the alveolar lining fluid. We examined the relative physiologic importance of the permeabilizing activity of SP-A in the lung, and the effects of oxidizing stimuli on the antimicrobial activity of SP-A and the alveolar lining fluid
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