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Published ahead of print on February 22, 2007, doi:10.1164/rccm.200610-1533OC

Am. J. Respir. Crit. Care Med., Volume 175, Number 9, May 2007, 958-966

A more recent version of this article appeared on May 1, 2007
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Submitted on October 24, 2006
Accepted on February 20, 2007

Importance of Phosphoinositide 3-Kinase {gamma} in the Host Defense Against Pneumococcal Infection

Ulrich A Maus1*, Myriam Backi2, Christine Winter1, Mrigank Srivastava1, Matthias K Schwarz3, Thomas Ruckle3, James C Paton4, David Briles5, Matthias Mack6, Tobias Welte1, Regina Maus1, Rainer M Bohle7, Werner Seeger2, Christian Rommel3, Emilio Hirsch8, Jurgen Lohmeyer2, and Klaus T Preissner9

1 Department of Pulmonary Medicine, Laboratory for Experimental Lung Research, Medical School Hannover, Hannover, Germany, 2 Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany, 3 Serono Pharmaceutical Research Institute, Serono International, Geneva, Switzerland, 4 School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia, 5 Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA, 6 Department of Internal Medicine, University of Regensburg, Regensburg, Germany, 7 Department of Pathology, Justus-Liebig-University, Giessen, Germany, 8 Department of Genetics, University of Torino, Turin, Italy, 9 Department of Biochemistry, Justus-Liebig-University, Giessen, Germany

* To whom correspondence should be addressed. E-mail: Maus.Ulrich{at}mh-hannover.de.

Rationale: Its pivotal role in leukocyte recruitment makes Phosphoinositide 3-kinase {gamma} (PI3K{gamma}) an attractive target for immunomodulatory therapy. However, interfering with PI3K{gamma} signaling might increase the risk of bacterial infections in humans. Objectives: We hypothesized that deletion or pharmacological inhibition of PI3K{gamma} would impair the lung inflammatory response to the prototypic Gram-positive bacterial pathogen, Streptococcus pneumoniae. Measurements: PI3K{gamma} KO and wild-type mice were infected with S. pneumoniae or challenged with the pneumococcal virulence factor, pneumolysin (PLY) and inflammatory leukocyte recruitment, bacterial pathogen elimination and resolution/repair processes were determined. Main Results: PI3K{gamma} KO mice challenged with PLY responded with lung edema and neutrophilic alveolitis, but showed a drop in alveolar macrophages and failed to recruit exudate macrophages when compared to wild-type mice. S. pneumoniae infected PI3K{gamma} KO mice and wild-type mice pretreated with the pharmacological inhibitor AS-605240 recruited similar numbers of neutrophils but substantially fewer exudate macrophages into their lungs than controls. They also displayed a significantly reduced lung pneumococcal clearance and showed an impaired resolution/repair process, leading to progressive pneumococcal pneumonia. Conclusions: PI3K{gamma} gene deletion or pharmacological inhibition of PI3K{gamma} leads to perturbations of critical innate immune responses of the lung to challenge with S. pneumoniae. These data are of clinical relevance for the treatment of chronic inflammatory diseases where pharmacological inhibition of PI3K{gamma} signaling to attenuate effector cell recruitment may have implications for innate immune surveillance of remote organ systems.
Key words: lung, infection, macrophage




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