Surfactant Protein-A-Deficient Mice Are Susceptible to<i>Pseudomonas aeruginosa</i>Infection

LeVine, Ann Marie; Kurak, Kim E.; Bruno, Michael D.; Stark, James M.; Whitsett, Jeffrey A.; Korfhagen, Thomas R.

doi:10.1165/ajrcmb.19.4.3254

Cited by 304 publications

(166 citation statements)

References 43 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…Macrophage infiltration and lung remodeling in SP-D (Ϫ͞Ϫ) mice were not associated with neutrophil infiltration or with marked differences in inflammatory levels of the acute phase proinflammatory mediators, tumor necrosis factor ␣, macrophage inflammatory protein 2, IL-1␤, and IL-6, but rather with increased hydrogen peroxide production and MMP activity in isolated alveolar macrophages. Although basal levels of IL-1␤ in lung homogenates were modestly increased in SP-D (Ϫ͞Ϫ) mice, IL-1␤ was not increased to levels typically detected in severe inflammation (18). It is unlikely, therefore, that the pulmonary abnormalities observed in SP-D (Ϫ͞Ϫ) mice were influenced or mediated by these relatively modest changes in IL-1␤.…”

Section: Discussionmentioning

confidence: 85%

Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice

Wert

Yoshida

LeVine

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

384

298

View full text Add to dashboard Cite

Targeted ablation of the surfactant protein D (SP-D) gene caused chronic inflammation, emphysema, and fibrosis in the lungs of SP-D (؊͞؊) mice. Although lung morphology was unperturbed during the first 2 weeks of life, airspace enlargement was observed by 3 weeks and progressed with advancing age. Inflammation consisted of hypertrophic alveolar macrophages and peribronchiolar-perivascular monocytic infiltrates. These abnormalities were associated with increased activity of the matrix metalloproteinases, MMP2 and MMP9, and immunostaining for MMP9 and MMP12 in alveolar macrophages. Hydrogen peroxide production by isolated alveolar macrophages also was increased significantly (10-fold). SP-D plays a critical role in the suppression of alveolar macrophage activation, which may contribute to the pathogenesis of chronic inflammation and emphysema.

show abstract

Section: Discussionmentioning

confidence: 85%

Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice

Wert

Yoshida

LeVine

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

384

298

View full text Add to dashboard Cite

show abstract

“…These mice clear the bacteria from the lungs at a slower rate than wild-type mice. Phagocytosis of P. aeruginosa by alveolar macrophages in SP-A Ϫ/Ϫ mice is also significantly decreased (30). Coadministration of SP-A with bacteria into the airway of SP-A Ϫ/Ϫ mice enhance phagocytosis of the bacteria by alveolar macrophages.…”

mentioning

confidence: 86%

Surfactant Proteins A and D Bind CD14 by Different Mechanisms

Sano¹,

Chiba²,

Iwaki³

et al. 2000

Journal of Biological Chemistry

196

204

View full text Add to dashboard Cite

Surfactant proteins A (SP-APulmonary surfactant is a complex mixture of lipids and proteins that functions to keep alveoli from collapsing at the end of expiration (1). Surfactant proteins A (SP-A) 1 and D (SP-D) are glycoprotein constituents of lung surfactant (2). SP-A and SP-D belong to the collectin subgroup of the C-type lectin superfamily along with mannose-binding proteins A and C, conglutinin, and CL43 (3). These proteins possess similar characteristic structures consisting of a short intersubunit disulfide forming the NH 2 terminus region, a collagen-like domain, a coiled-coil motif neck domain, and a carbohydrate recognition domain (CRD) (2). The CRD region of SP-A is essential for dipalmitoylphosphatidylcholine and galactosylceramide binding, liposome aggregation, the inhibitory effect on lipid secretion, and the augmentation of lipid uptake by alveolar type II cells (4 -11). Likewise, the CRD region of SP-D functions in the recognition of the ligands phosphatidylinositol and glucosylceramide (12,13). In addition to their interaction with lipids and alveolar type II cells, lung collectins interact with macrophages (14 -16) and enhance phagocytosis of a wide spectrum of microorganism (17-25). Lung collectins are now thought to be important components of the innate immune system of the lung (26 -28).Studies with transgenic mice provide strong support for a role of pulmonary collectins in host defense properties. Mice homozygous for null alleles of SP-A exhibit increased susceptibility to group B streptococcal and Pseudomonas aeruginosa infections (29 -31). These mice clear the bacteria from the lungs at a slower rate than wild-type mice. Phagocytosis of P. aeruginosa by alveolar macrophages in SP-A Ϫ/Ϫ mice is also significantly decreased (30). Coadministration of SP-A with bacteria into the airway of SP-A Ϫ/Ϫ mice enhance phagocytosis of the bacteria by alveolar macrophages. Secretion of proinflammatory cytokines into the alveolar space is significantly elevated in SP-A Ϫ/Ϫ mice compared with SP-A ϩ/ϩ mice after intratracheal challenge with P. aeruginosa. These studies suggest that SP-A modulates innate immune responses by several different mechanisms. Although these in vivo studies explicitly indicate that SP-A plays a crucial role in host defense of the lung, the molecular basis of SP-A-mediated modification of inflammatory responses remains to be elucidated.Lipopolysaccharide (LPS), derived from Gram-negative bacteria, is a potent stimulator of inflammation (32). Smooth LPS is composed of O-antigen, core oligosaccharides, and lipid A, while rough LPS lacks O-antigen and a part of the core oligosaccharides (33). The cellular responses to physiological amounts of LPS depend on membrane CD14 that is phosphatidylinositol-anchored to the plasma membrane of myeloid cells (34). A soluble form of CD14 which exists in serum also facilitates the responsiveness of the cells to LPS (35,36). The principal role of CD14 is to bind LPS, but how CD14 acts in transmitting LPS signal remains to be resolved. Recently, ...

show abstract

“…Various cellular binding sites for SP-A and SP-D have been identified on alveolar macrophages or, in the case of SP-A, on type II epithelial cells (13,15,16). The critical role of SP-A in host defense was supported by the observation that SP-A-deficient mice are susceptible to infections by both group B streptococcus and Pseudomonas aeruginosa in vivo (17,18).…”

mentioning

confidence: 99%