We investigated whether nitration of surfactant apoprotein (SP) A alters its ability to bind to mannose-containing saccharides on Pneumocystis carinii and its potential role in the mediation of P. carinii adherence to alveolar macrophages. Human SP-A was nitrated by incubation with tetranitromethane at pH 8.0 or synthetic peroxynitrite (ONOO-) at pH 7.4, which resulted in significant nitration of tyrosines in its carbohydrate recognition domain [0.63 ± 0.001 (SE) and 1.25 ± 0.02 mol nitrotyrosine/mol monomeric SP-A, respectively; n = 3 samples]. Binding of SP-A to P. carinii was calcium dependent and competitively inhibited by α-methyl-D-mannopyranoside. Nitration of SP-A by ONOO- or tetranitromethane decreases its binding to P. carinii by increasing its dissociation constant from 7.8 x 10-9 to 1.6 x 10-8 or 2.4 x 10-8 M, respectively, without significantly affecting the number of binding sites (7.1 x 106/P. carinii organisms, assuming that the native molecular mass of oligomeric SP-A is 650 kDa). Furthermore, ONOO-- nitrated SP-A failed to mediate the adherence and phagocytosis of P. carinii to rat alveolar macrophages as observed with normal SP-A. Binding of SP-A to rat alveolar macrophages was not altered by nitration. These results indicate that nitration of SP-A interferes with its ability to serve as a ligand for P. carinii adherence to alveolar macrophages at the site of the SP-A molecule-P. carinii interaction.