Urokinase-type plasminogen activator in inflammatory cell recruitment and host defense against Pneumocystis carinii in mice

Effective host defense against Pneumocystis carinii depends upon the integr ated actions of inflammatory cells and mediators in the lungs. Using immuno competent and immunosuppressed mice, our laboratory has defined inflammator y changes in the lungs in response to P. carinii. However, the essential mo lecules and mechanisms required for cellular recruitment and for host defen se against P. carinii are undefined. We hypothesized that urokinase-type pl asminogen activator (uPA), a protease intimately involved in inflammatory c ell migration and activation, is required for clearance of P. carinii. To t est this hypothesis in vivo, we compared the intensity of P. carinii infect ion and inflammation in the lungs of mice lacking the uPA gene (uPA knockou t mice) and in the lungs of wild-type mice. After intratracheal inoculation with P. carinii organisms, uPA knockout mice developed uniformly heavy P. carinii pneumonia while wild-type mice cleared the P. carinii inoculum. Bro nchoalveolar lavage fluid from uPA knockout mice contained significantly sm aller numbers of cells than did lavage fluid from wild-type mice. We conclu de that deletion of the uPA gene prevents the clearance of P. carinii and r educes inflammatory cell recruitment. Therefore, uPA is an important partic ipant in the network of inflammatory events required for the clearance of P . carinii, confirming an important role for this molecule in pulmonary host defense against opportunistic pathogens.