PULMONARY SURFACTANT INHIBITS MONOCYTE BACTERICIDAL FUNCTIONS BY ALTERING ACTIVATION OF PROTEIN KINASE-A AND KINASE-C

Pulmonary surfactant, the main function of which is to reduce surface tension in the alveoli, is also known to affect the functions of monoc ytes. Two protein kinases play a role in the regulation of the bacteri cidal functions of phagocytes, i.e. cAMP-dependent protein kinase A (P KA), which is involved in inhibition, and Ca2+/phospholipid-dependent PKC, which is involved in stimulation of these functions. In the prese nt study we investigated whether altered activation of PKA and/or PKC plays a role in the surfactant-induced inhibition of both the intracel lular killing of Staphylococcus aureus and the production of reactive oxygen intermediates (ROI) by monocytes. The significance of increased activation of PKA was demonstrated by the following findings. Firstly , surfactant induced a sustained increase in the intracellular cAMP co ncentration in monocytes. Secondly, dibutyryl-cAMP (db-cAMP), a membra ne-permeable cAMP analogue, mimicked the inhibitory effects of surfact ant on both the killing capacity and the production of ROI by monocyte s. Thirdly, an inhibitor of PKA partially restored the impaired bacter icidal functions of monocytes incubated with surfactant. The involveme nt of decreased activation of PKC in the impaired bactericidal functio ns of monocytes incubated with surfactant was evident from two finding s. Firstly, surfactant attenuated the phorbol myristate acetate (PMA)- mediated translocation of PKC. Secondly, surfactant inhibited the prod uction of O-2(-) by monocytes upon stimulation with PMA. Therefore, th e mechanism involved in the surfactant-induced inhibition of the bacte ricidal functions of monocytes comprises both activation of an inhibit ory pathway, which includes cAMP and PKA, and inactivation of a stimul atory pathway, in which PKC is involved.