| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom
Regulation of the inflammatory infiltrate is critical to the successful outcome of pneumonia. Alveolar macrophage apoptosis is a feature of pneumococcal infection and aids disease resolution. The host benefits of macrophage apoptosis during the innate response to bacterial infection are incompletely defined. Because NO is required for optimal macrophage apoptosis during pneumococcal infection, we have explored the role of macrophage apoptosis in regulating inflammatory responses during pneumococcal pneumonia, using inducible NO synthase (iNOS)-deficient mice. iNOS–/– mice demonstrated decreased numbers of apoptotic macrophages as compared with wild-type C57BL/6 mice following pneumococcal challenge, greater recruitment of neutrophils to the lung and enhanced expression of TNF-
. Pharmacologic inhibition of iNOS produced similar results. Greater pulmonary inflammation was associated with greater levels of early bacteremia, IL-6 production, lung inflammation, and mortality within the first 48 h in iNOS–/– mice. Labeled apoptotic alveolar macrophages were phagocytosed by resident macrophages in the lung and intratracheal instillation of exogenous apoptotic macrophages decreased neutrophil recruitment in iNOS–/– mice and decreased TNF- mRNA in lungs and protein in bronchial alveolar lavage, as well as chemokines and cytokines including IL-6. These changes were associated with a lower probability of mice becoming bacteremic. This demonstrates the potential of apoptotic macrophages to down-regulate the inflammatory response and for the first time in vivo demonstrates that clearance of apoptotic macrophages decreases neutrophil recruitment and invasive bacterial disease during pneumonia.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Wellcome Trust Advanced and Senior Clinical Fellowships (to D.H.D.), Nos. 065054 and 076945.
2 Address correspondence and reprint requests to Dr. David H. Dockrell, Division of Genomic Medicine, F-Floor, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, U.K. E-mail address: d.h.dockrell{at}sheffield.ac.uk
3 Abbreviations used in this paper: AM, alveolar macrophage; iNOS, inducible NO synthase; BAL, bronchial alveolar lavage; DAPI, 4',6'-diamidino-2-phenylindole; qRT-PCR, quantitative RT-PCR; PMN, polymorphonuclear neutrophil.
This article has been cited by other articles:
|
|
 |
|
  S. Brennan, P. D. Sly, C. L. Gangell, N. Sturges, K. Winfield, M. Wikstrom, S. Gard, J. W. Upham, and on behalf of AREST CF Alveolar macrophages and CC chemokines are increased in children with cystic fibrosis Eur. Respir. J., September 1, 2009; 34(3): 655 - 661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Kirby, M. C. Coles, and P. M. Kaye Alveolar Macrophages Transport Pathogens to Lung Draining Lymph Nodes J. Immunol., August 1, 2009; 183(3): 1983 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Li, Y. Zhang, B. Dorweiler, D. Cui, T. Wang, C. W. Woo, C. S. Brunkan, C. Wolberger, S.-i. Imai, and I. Tabas Extracellular Nampt Promotes Macrophage Survival via a Nonenzymatic Interleukin-6/STAT3 Signaling Mechanism J. Biol. Chem., December 12, 2008; 283(50): 34833 - 34843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Xu, D. Droemann, J. Rupp, H. Shen, X. Wu, T. Goldmann, S. Hippenstiel, P. Zabel, and K. Dalhoff Modulation of the Inflammatory Response to Streptococcus pneumoniae in a Model of Acute Lung Tissue Infection Am. J. Respir. Cell Mol. Biol., November 1, 2008; 39(5): 522 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Zhou, R. P. Barrett, S. A. McClellan, Y. Zhang, E. A. Szliter, N. van Rooijen, and L. D. Hazlett Substance P Delays Apoptosis, Enhancing Keratitis after Pseudomonas aeruginosa Infection Invest. Ophthalmol. Vis. Sci., October 1, 2008; 49(10): 4458 - 4467. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-S. Choi, E.-K. Song, and C.-Y. Yim Cytokines secreted by IL-2-activated lymphocytes induce endogenous nitric oxide synthesis and apoptosis in macrophages J. Leukoc. Biol., June 1, 2008; 83(6): 1440 - 1450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Taut, C. Winter, D. E. Briles, J. C. Paton, J. W. Christman, R. Maus, R. Baumann, T. Welte, and U. A. Maus Macrophage Turnover Kinetics in the Lungs of Mice Infected with Streptococcus pneumoniae Am. J. Respir. Cell Mol. Biol., January 1, 2008; 38(1): 105 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Winter, K. Taut, F. Langer, M. Mack, D. E. Briles, J. C. Paton, R. Maus, M. Srivastava, T. Welte, and U. A. Maus FMS-Like Tyrosine Kinase 3 Ligand Aggravates the Lung Inflammatory Response to Streptococcus pneumoniae Infection in Mice: Role of Dendritic Cells J. Immunol., September 1, 2007; 179(5): 3099 - 3108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-P. Erwig and P. M. Henson Immunological Consequences of Apoptotic Cell Phagocytosis Am. J. Pathol., July 1, 2007; 171(1): 2 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Marks, T. Burns, M. Abadi, B. Seyoum, J. Thornton, E. Tuomanen, and L.-a. Pirofski Influence of Neutropenia on the Course of Serotype 8 Pneumococcal Pneumonia in Mice Infect. Immun., April 1, 2007; 75(4): 1586 - 1597. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
