Maus, Ulrich A. and Backi, Myriam and Winter, Christine and Srivastava, Mrigank and Schwarz, Matthias K. and Rueckle, Thomas and Paton, James C. and Briles, David and Mack, Matthias and Welte, Tobias and Maus, Regina and Bohle, Rainer M. and Seeger, Werner and Rommel, Christian and Hirsch, Emilio and Lohmeyer, Juergen and Preissner, Klaus T. (2007) Importance of phosphoinositide 3-kinase gamma in the host defense against pneumococcal infection. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 175 (9). pp. 958-966. ISSN 1073-449X,
Full text not available from this repository. (Request a copy)Abstract
Rationale: The pivotal role of phosphoinositide 3-kinase gamma (PI3K gamma) in leukocyte recruitment makes it 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 pharmacologic inhibition of PI3K gamma would impair the lung inflammatory response to the prototypic gram-positive bacterial pathogen Streptococcus pneumoniae. Methods: PI3K gamma knockout (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. Measurements and 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 with wild-type mice. S. pneumoniae-infected PI3K gamma KID mice and wild-type mice pretreated with the pharmacologic inhibitor AS-605240 recruited similar numbers of neutrophils but substantially fewer exudate macrophages into their lungs than control animals. 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 pharmacologic 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 pharmacologic inhibition of PI3K gamma signaling to attenuate effector cell recruitment may have implications for innate immune surveillance of remote organ systems.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RESIDENT ALVEOLAR MACROPHAGES; STREPTOCOCCUS-PNEUMONIAE; LUNG INFLAMMATION; PNEUMOLYSIN; PI3K-GAMMA; TRAFFICKING; LEUKOCYTE; MIGRATION; SPACE; MICE; lung; infection; macrophage |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 10 Dec 2020 10:27 |
| Last Modified: | 10 Dec 2020 10:27 |
| URI: | https://pred.uni-regensburg.de/id/eprint/32777 |
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