Surfactant protein A enhances mycobacterial killing by rat macrophages through a nitric oxide-dependent pathway.
Surfactant-associated protein A (SP-A) is involved in surfactant homeostasis and host defense in the lung. We have previously demonstrated that SP-A specifically binds to and enhances the ingestion of bacillus Calmette-Guerin (BCG) organisms by macrophages. In the current study, we investigated the effect of SP-A on the generation of inflammatory mediators induced by BCG and the subsequent fate of ingested BCG organisms. Rat macrophages were incubated with BCG in the presence and absence of SP-A. Noningested BCG organisms were removed, and the release of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide were measured at varying times. TNF-alpha and nitric oxide production induced by BCG were enhanced by SP-A. In addition, SP-A enhanced the BCG-induced increase in the level of inducible nitric oxide synthase protein. Addition of antibodies directed against SPR210, a specific macrophage SP-A receptor, inhibited the SP-A-enhanced mediator production. BCG in the absence of SP-A showed increased growth over a 5-day period, whereas inclusion of SP-A dramatically inhibited BCG growth. Inhibition of nitric oxide production blocked BCG killing in the presence and absence of SP-A. These results demonstrate that ingestion of SP-A-BCG complexes by rat macrophages leads to production of inflammatory mediators and increased mycobacterial killing.
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA.
L F
LF
Weikert
J P
JP
Lopez
R
R
Abdolrasulnia
Z C
ZC
Chroneos
V L
VL
Shepherd
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001500:BCG Vaccine / Q000276:immunology; D052160:Benzothiazoles; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D011510:Proteolipids / Q000378:metabolism* / Q000494:pharmacology; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013843:Thiazines / Q000037:antagonists & inhibitors / Q000378:metabolism; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014498:Uracil / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000906:Antibodies; D001500:BCG Vaccine; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D013843:Thiazines; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C088258:SPR 210; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D014498:Uracil; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat