GM-CSF modulates pulmonary resistance to influenza A infection

[tetano]

Antiviral Res. 2011 Sep 8. [Epub ahead of print]
GM-CSF modulates pulmonary resistance to influenza A infection.
Sever-Chroneos Z, Murthy A, Davis J, Florence JM, Kurdowska A, Krupa A, Tichelaar JW, White MR, Hartshorn KL, Kobzik L, Whitsett JA, Chroneos ZC.
Source

University of Texas Health Science Center at Tyler, Center of Biomedical Research, 11937 US HWY 271, Tyler, TX 75708-3154, United States.
Abstract

Alveolar type II epithelial or other pulmonary cells secrete GM-CSF that regulates surfactant catabolism and mucosal host defense through its capacity to modulate the maturation and activation of alveolar macrophages. GM-CSF enhances expression of scavenger receptors MARCO and SR-A. The alveolar macrophage SP-R210 receptor binds the surfactant collectin SP-A mediating clearance of respiratory pathogens. The current study determined the effects of epithelial-derived GM-CSF in host resistance to influenza A pneumonia. The results demonstrate that GM-CSF enhanced resistance to infection with 1.9?10(4)ffc of the mouse-adapted influenza A/Puerto Rico/8/34 (PR8) H1N1 strain, as indicated by significant differences in mortality and mean survival of GM-CSF-deficient (GM(-/-)) mice compared to GM(-/-) mice in which GM-CSF is expressed at increased levels. Protective effects of GM-CSF were observed both in mice with constitutive and inducible GM-CSF expression under the control of the pulmonary-specific SFTPC or SCGB1A1 promoters, respectively. Mice that continuously secrete high levels of GM-CSF developed desquamative interstitial pneumonia that impaired long-term recovery from influenza. Conditional expression of optimal GM-CSF levels at the time of infection, however, resulted in alveolar macrophage proliferation and focal lymphocytic inflammation of distal airways. GM-CSF enhanced alveolar macrophage activity as indicated by increased expression of SP-R210 and CD11c. Infection of mice lacking the GM-CSF-regulated SR-A and MARCO receptors revealed that MARCO decreases resistance to influenza in association with increased levels of SP-R210 in MARCO(-/-) alveolar macrophages. In conclusion, GM-CSF enhances early host resistance to influenza. Targeting of MARCO may reinforce GM-CSF-mediated host defense against pathogenic influenza.

Copyright ? 2011 Elsevier B.V. All rights reserved.

PMID:
21925209
[PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/21925209

 

[tetano]

Re: GM-CSF modulates pulmonary resistance to influenza A infection

Am J Respir Crit Care Med. 2011 Jul 15;184(2):259-68. Epub 2011 Apr 7.
GM-CSF in the lung protects against lethal influenza infection.
Huang FF, Barnes PF, Feng Y, Donis R, Chroneos ZC, Idell S, Allen T, Perez DR, Whitsett JA, Dunussi-Joannopoulos K, Shams H.
Source

Center for Pulmonary and Infectious Disease Control, University of Texas Health Science Center at Tyler, Texas, USA.
Abstract
RATIONALE:

Alveolar macrophages contribute to host defenses against influenza in animal models. Enhancing alveolar macrophage function may contribute to protection against influenza.
OBJECTIVES:

To determine if increased expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) in the lung increases resistance to influenza.
METHODS:

Wild-type mice and transgenic mice that expressed GM-CSF in the lung were infected with influenza virus, and lung pathology, weight loss, and mortality were measured. We also administered GM-CSF to the lungs of wild-type mice that were infected with influenza virus.
MEASUREMENTS AND MAIN RESULTS:

Wild-type mice all died after infection with different strains of influenza virus, but all transgenic mice expressing GM-CSF in the lungs survived. The latter also had greatly reduced weight loss and lung injury, and showed histologic evidence of a rapid host inflammatory response that controlled infection. The resistance of transgenic mice to influenza was abrogated by elimination of alveolar phagocytes, but not by depletion of T cells, B cells, or neutrophils. Transgenic mice had far more alveolar macrophages than did wild-type mice, and they were more resistant to influenza-induced apoptosis. Delivery of intranasal GM-CSF to wild-type mice also conferred resistance to influenza.
CONCLUSIONS:

GM-CSF confers resistance to influenza by enhancing innate immune mechanisms that depend on alveolar macrophages. Pulmonary delivery of this cytokine has the potential to reduce the morbidity and mortality due to influenza virus.
Comment in

Am J Respir Crit Care Med. 2011 Jul 15;184(2):157-8.

PMID:
21474645
[PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/21474645