Surfactant protein A enhances mycobacterial killing by rat macrophages through a nitric oxide-dependent pathway

Abstract

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.

Surfactant protein D inhibits TNF-α production by macrophages and dendritic cells in mice

“…In vitro studies conducted on the direct effects of lung collectins on alveolar macrophages have been somewhat controversial because they found both stimulation [27][28][29][30] and inhibition 27,[31][32][33] of proinflammatory functions, including TNF-α production. 34 Only a few studies described the effects of SP-A and SP-D on dendritic cell function.…”

Surfactant Protein A (SP-A)-mediated Clearance of Staphylococcus aureus Involves Binding of SP-A to the Staphylococcal Adhesin Eap and the Macrophage Receptors SP-A Receptor 210 and Scavenger Receptor Class A

“…Earlier studies showed that SP-R210 mediates phagocytosis and killing of SP-A-opsonized Mycobacterium bovis BCG (SP-A-BCG) by bone marrowderived macrophages (23). These studies showed that ligation of SP-R210 with SP-A-BCG complexes enhanced expression of TNF␣ and nitric oxide that enabled macrophages to control mycobacterial growth (23,26). On the other hand, SP-R210 can control the level of inflammatory cells and mediators in the presence of mycobacterial extracts, suggesting a secondary role of SP-R210 in immune homeostasis (27).…”

Phenotypic consequences of lung-specific inducible expression of FGF-3

“…The late induction of these cytokines indicates that their increase may not be the primary response to FGF-3 induction but a response to an alteration in pulmonary gene expression. SP-A has been found to promote macrophage phagocytosis (32) and chemotaxis (33). Induction of SP-A by FGF-3 may play a role in the FAM phenotype.…”

“…First, the chronic high level of the expression of FGF-3 could alter the differentiation of Clara cells, which could be manifested in a reduction in the expression of these cell-specific markers. Second, inflammatory cytokines may have affected expression of these genes directly and͞or the phenotype of airway epithelial cells (32,33). Finally, and more likely, the increase in the number of alveolar type II cells could result in the dilution of Clara cell-specific mRNA, because the proportion of airway cells in the lung could decrease with the increase in distal cells.…”

“…An increase in surfactant protein mRNA was correlated best with the induction of FGF-3. FGF-3 stimulation of surfactant protein production may result directly in the recruitment of macrophages into the lung (32,33). Alternatively, the FAM recruitment may be an indirect result of increased surfactant production by the alveolar Type II cells.…”