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Macrophage Dysfunction and Susceptibility to Pulmonary Pseudomonas aeruginosa Infection in Surfactant Protein C-Deficient Mice¹

Stephan W. Glasser^2,*, Albert P. Senft^3,*, Jeffrey A. Whitsett^*, Melissa D. Maxfield^*, Gary F. Ross^*, Theresa R. Richardson^*, Daniel R. Prows, Yan Xu^* and Thomas R. Korfhagen^*

^* Division of Pulmonary Biology and Division of Human Genetics, Department of Pediatrics, Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229

To determine the role of surfactant protein C (SP-C) in host defense, SP-C-deficient (Sftpc^–/–) mice were infected with the pulmonary pathogen Pseudomonas aeruginosa by intratracheal injection. Survival of young, postnatal day 14 Sftpc^–/– mice was decreased in comparison to Sftpc^+/+ mice. The sensitivity to Pseudomonas bacteria was specific to the 129S6 strain of Sftpc^–/– mice, a strain that spontaneously develops interstitial lung disease-like lung pathology with age. Pulmonary bacterial load and leukocyte infiltration were increased in the lungs of Sftpc^–/– mice 24 h after infection. Early influx of polymorphonuclear leukocytes in the lungs of uninfected newborn Sftpc^–/– mice relative to Sftpc^+/+ mice indicate that the lack of SP-C promotes proinflammatory responses in the lung. Mucin expression, as indicated by Alcian blue staining, was increased in the airways of Sftpc^–/– mice following infection. Phagocytic activity of alveolar macrophages from Sftpc^–/– mice was reduced. The uptake of fluorescent beads in vitro and the number of bacteria phagocytosed by alveolar macrophages in vivo was decreased in the Sftpc^–/– mice. Alveolar macrophages from Sftpc^–/– mice expressed markers of alternative activation that are associated with diminished pathogen response and advancing pulmonary fibrosis. These findings implicate SP-C as a modifier of alveolar homeostasis. SP-C plays an important role in innate host defense of the lung, enhancing macrophage-mediated Pseudomonas phagocytosis, clearance and limiting pulmonary inflammatory responses.

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 Grants HL50046 and HL61646 (to S.W.G., J.A.W., and D.R.P.), HL58795 (to T.R.K.), and by the Parker B. Francis Foundation (to A.P.S.).

² Address correspondence and reprint requests to Dr. Stephan W. Glasser, Division of Pulmonary Biology, MLC 7029, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039. E-mail address: steve.glasser{at}cchmc.org

³ Current address: Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive, SE, Albuquerque, NM 87108.

⁴ Abbreviations used in this paper: SP-C, surfactant protein C; SP-A, surfactant protein A; SP-D surfactant protein D; ILD, interstitial lung disease; BALF, bronchoalveolar lavage fluid; MMP, matrix metalloproteinase; PND14, postnatal day 14; AAM, alternatively activated macrophage.