The purpose of this study was to investigate how surfactant membranes can be perturbed by C-reactive protein (CRP) and whether surfactant protein A (SP-A) might overcome CRP-induced surfactant membrane alterations. The effect of CRP on surfactant surface adsorption was evaluated in vivo after intratracheal instillation of CRP into rat lungs. Insertion of CRP into surfactant membranes was investigated through monolayer techniques. The effect of CRP on membrane structure was studied through differential scanning calorimetry and fluorescence spectroscopy and microscopy using large and giant unilamellar vesicles. Our results indicate that CRP inserts into surfactant membranes and drastically increases membrane fluidity, resulting in surfactant inactivation. At 10% CRP/phospholipid weight ratio, CRP causes disappearance of liquid-ordered/liquid-disordered phase coexistence distinctive of surfactant membranes. SP-A, the most abundant surfactant lipoprotein structurally similar to C1q, binds to CRP (K(d)=56±8 nM), as determined by solid-phase binding assays and dynamic light scattering. This novel SP-A/CRP interaction reduces CRP insertion and blocks CRP effects on surfactant membranes. In addition, intratracheal coinstillation of SP-A+CRP into rat lungs prevents surfactant inhibition induced by CRP, indicating that SP-A/CRP interactions might be an important factor in vivo in controlling harmful CRP effects in the alveolus.