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Published ahead of print on May 15, 2008, doi:10.1165/rcmb.2007-0328OC

Am. J. Respir. Cell Mol. Biol., Volume 39, Number 5, November 2008, 522-529

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Submitted on September 6, 2007
Revised on May 15, 2008

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

Feng Xu1, Daniel Droemann2, Jan Rupp3, Huahao Shen4, Xiaohong Wu5, Torsten Goldmann6, Stefan Hippenstiel7, Peter Zabel8, and Klaus Dalhoff9*

1 Medical Clinic III, University of Schleswig-Holstein, Campus Lubeck, Lubeck, Schleswig-Holstein, Germany; Department of Respiratory Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China, 2 Research Center Borstel, Medical Clinic, Borstel, Schleswig-Holstein, Germany, 3 University of Schleswig-Holstein, Institute of Medical Microbiology and Hygiene, Campus Lubeck, Lubeck, Schleswig-Holstein, Germany, 4 Department of Respiratory Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China, 5 Medical Clinic III, University of Schleswig-Holstein, Campus Lubeck, Lubeck, Schleswig-Holstein, Germany; Department of Pulmonary Medicine, Sir Run Run Shaw Hospital, Zhejiang Univeristy School of Medicine, Hangzhou, Zhejiang, China, 6 Clinical and Experimental Pathology, Research Center Borstel, Borstel, Schleswig-Holstein, Germany, 7 Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charite-University, Berlin, Berlin, Germany, 8 Medical Clinic III, University of Schleswig-Holstein, Campus Lubeck, Lubeck, Schleswig-Holstein, Germany; Research Center Borstel, Medical Clinic, Borstel, Schleswig-Holstein, Germany, 9 Medical Clinic III, University of Schleswig-Holstein, Campus Lubeck, Lubeck, Schleswig-Holstein, Germany

* To whom correspondence should be addressed. E-mail: klaus.dalhoff{at}medinf.mu-luebeck.de.

Rationale: 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. Objectives: 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. Measurements and Main results: 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 80-90% of AMs and 15-30% 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. 30-50% of AMs and 10-20% of AECs showed evidence of apoptosis 24 h 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. Conclusions: 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.






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