Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. The lung plays an important role in initiating innate immune responses and clearing microbes. However，little is known concerning S. Pneumoniae-host cell interaction within the human pulmonary compartment. Toll-like receptor(TLR)2 is a key pattern recognition receptor for pneumococci-related cell activation. Mitogen-activated protein kinases(MAPKs)are involved in TLR-mediated signal transduction and contribute to nuclear factor(NF)-κB transactivation and inflammatory cytokine expression. In the present study，we established a novel model of acute S. Pneumoniae infection(ASIM)in vital lung specimens from pulmonary lobectomy. In situ hybridization analysis showed that S. Pneumoniae DNA was detected in 80-90％ alveolar macrophages and 15-30％ of alveolar epithelial cells type II 24h after stimulation(n=26). Macrophage depletion with Clodronate liposomes resulted in a decreased TNF-αrelease in the ASIM. In addition，enhanced phosphorylation of p38-MAPK and increased TLR-2 and 4 mRNA expression were observed in infected lung tissue using Western blot and RT-PCR. Inhibition of p38-MAPK signaling reduced inflammatory cytokine release from lung tissue in contrast to TLR2 and TLR4 blockade. To confirm findings from the ASIM，we further analyzed lung epithelial cells，alveolar macrophages and blood leukocytes as potential sources of inflammatory cytokines. Altogether，alveolar macrophages are the most important host cells in the human ASIM and are the main source of proinflammatory cytokine release.
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