ALVEOLAR MACROPHAGES ARE REQUIRED FOR PROTECTIVE PULMONARY DEFENSES IN MURINE KLEBSIELLA PNEUMONIA - ELIMINATION OF ALVEOLAR MACROPHAGES INCREASES NEUTROPHIL RECRUITMENT BUT DECREASES BACTERIAL CLEARANCE AND SURVIVAL

To study the in vivo role of alveolar macrophages (AM) in gram-negativ e bacterial pneumonia in mice, AM were eliminated by the intratracheal (i.t.) administration of dichloromethylene diphosphonate encapsulated liposomes. Subsequently, the AM-depleted mice were infected i.t. with 100 CFU of Klebsiella pneumoniae, and the effects of AM depletion on survival, bacterial clearance, and neutrophil (polymorphonuclear leuko cyte [PMN]) recruitment were assessed, It was shown that depletion of AM decreases survival dramatically, with 100% lethality at day 3 posti nfection, versus 100% long-term survival in the control group, This in creased mortality was accompanied by 20- to 27- and 3- to 10-fold incr eases in the number of K. pneumoniae CFU in lung and plasma, respectiv ely, compared to those in nondepleted animals, This decreased bacteria l clearance was not due to an impaired PMN recruitment; on the contrar y, the K. pneumoniae-induced PMN recruitment in AM-depleted lungs was sevenfold greater 48 h postinfection than that in control infected lun gs, Together with an increased PMN infiltration, 3- and 10-fold increa ses in lung homogenate tumor necrosis factor alpha (TNF-a) and macroph age inflammatory protein 2 (MIP-2) levels, respectively, were measured , Neutralization of tnf-alpha or MIP-2, 2 h before infection, reduced the numbers of infiltrating PMN by 41.6 and 64.2%, respectively, indic ating that these cytokines mediate PMN influx in infected lungs, rathe r then just being produced by the recruited PMN themselves, Our studie s demonstrate, for the first time, the relative importance of the AM i n the containment and clearance of bacteria in the setting of Klebsiel la pneumonia.