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Modulation of the Inflammatory Response to Streptococcus pneumoniae in a Model of Acute Lung Tissue Infection

¹ Medical Clinic III, and ⁴ Institute of Medical Microbiology and Hygiene, University of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; ² Department of Respiratory Medicine, Second Affiliated Hospital, and ⁵ Department of Pulmonary Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; ³ Medical Clinic, and ⁶ Clinical and Experimental Pathology, Research Center Borstel, Borstel, Germany; and ⁷ Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité-University, Berlin, Germany

Correspondence and requests for reprints should be addressed to Klaus Dalhoff, M.D., Medical Clinic III, Campus Lübeck, University of Schleswig-Holstein, 23538 Lübeck, Germany. E-mail: klaus.dalhoff{at}uni-luebeck.de

Streptococcus pneumoniae is the leading pathogen of community-acquired pneumonia and is a main cause of infectious deaths. However, little is known about host–pathogen interaction in human lung tissue. We tested the hypothesis that human alveolar macrophages (AMs) and alveolar epithelial cells (AECs) are important for initiating the host response against S. pneumoniae, and we evaluated the role of Toll-like receptor (TLR) 2, TLR4, and p38 mitogen-activated protein kinase (MAPK) signaling in the inflammatory response after pneumococcal infection. We established a novel model of acute S. pneumoniae infection using vital human lung specimens. In situ hybridization analysis showed that S. pneumoniae DNA was detected in 80 to 90% of AMs and 15 to 30% of AECs after in vitro infection accompanied by increased expression of inflammatory cytokines. Enhanced phosphorylation of p38 MAPK and increased TLR2 and 4 mRNA expression were observed in infected lung tissue. Thirty to fifty percent of AMs and 10 to 20% of AECs showed evidence of apoptosis 24 hours after pneumococcal infection. After macrophage deactivation with Clodronate/liposomes, infected lung tissue exhibited a significantly decreased release of inflammatory mediators. Inhibition of p38 MAPK signaling markedly reduced inflammatory cytokine release from human lungs, whereas TLR2 blockade revealed only minor effects. AMs are central resident immune cells during S. pneumoniae infection and are the main source of early proinflammatory cytokine release. p38 MAPK holds a major role in pathogen-induced pulmonary cytokine release and is a potential molecular target to modulate overwhelming lung inflammation.

Key Words: Streptococcus pneumoniae • pulmonary inflammatory response • alveolar macrophages • Toll-like receptor • mitogen-activated protein kinase