Abstract |
Pulmonary surfactant protein-C (SP-C) gene-targeted mice (Sftpc(-/-)) develop progressive lung inflammation and remodeling. We hypothesized that SP-C deficiency reduces the ability to suppress repetitive inflammatory injury. Sftpc(+/+) and Sftpc(-/-) mice given three doses of bacterial LPS developed airway and airspace inflammation, which was more intense in the Sftpc(-/-) mice at 3 and 5 days after the final dose. Compared with Sftpc(+/+)mice, inflammatory injury persisted in the lungs of Sftpc(-/-) mice 30 days after the final LPS challenge. Sftpc(-/-) mice showed LPS-induced airway goblet cell hyperplasia with increased detection of Sam pointed Ets domain and FoxA3 transcription factors. Sftpc(-/-) type II alveolar epithelial cells had increased cytokine expression after LPS exposure relative to Sftpc(+/+) cells, indicating that type II cell dysfunction contributes to inflammatory sensitivity. Microarray analyses of isolated type II cells identified a pattern of enhanced expression of inflammatory genes consistent with an intrinsic low-level inflammation resulting from SP-C deficiency. SP-C-containing clinical surfactant extract ( Survanta) or SP-C/ phospholipid vesicles blocked LPS signaling through the LPS receptor ( Toll-like receptor [TLR] 4/CD14/MD2) in human embryonic kidney 293T cells, indicating that SP-C blocks LPS-induced cytokine production by a TLR4-dependent mechanism. Phospholipid vesicles alone did not modify the TLR4 response. In vivo deficiency of SP-C leads to inflammation, increased cytokine production by type II cells, and persistent inflammation after repetitive LPS stimulation.
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Authors | Stephan W Glasser, Melissa D Maxfield, Teah L Ruetschilling, Henry T Akinbi, John E Baatz, Joseph A Kitzmiller, Kristen Page, Yan Xu, Erik L Bao, Thomas R Korfhagen |
Journal | American journal of respiratory cell and molecular biology
(Am J Respir Cell Mol Biol)
Vol. 49
Issue 5
Pg. 845-54
(Nov 2013)
ISSN: 1535-4989 [Electronic] United States |
PMID | 23795648
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Biological Products
- Cytokines
- Endotoxins
- Foxa3 protein, mouse
- Inflammation Mediators
- Intercellular Signaling Peptides and Proteins
- Lipopolysaccharide Receptors
- Peptides
- Proto-Oncogene Proteins c-ets
- Pulmonary Surfactant-Associated Protein C
- Sftpc protein, mouse
- Spdef protein, mouse
- Tlr4 protein, mouse
- Toll-Like Receptor 4
- Hepatocyte Nuclear Factor 3-gamma
- endotoxin, Escherichia coli
- beractant
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Topics |
- Alveolar Epithelial Cells
(immunology, metabolism, pathology)
- Animals
- Biological Products
(pharmacology)
- Cytokines
(metabolism)
- Disease Models, Animal
- Endotoxins
- Gene Expression Regulation
- Goblet Cells
(immunology, metabolism, pathology)
- HEK293 Cells
- Hepatocyte Nuclear Factor 3-gamma
(metabolism)
- Humans
- Hyperplasia
- Immunity, Innate
- Inflammation Mediators
(metabolism)
- Intercellular Signaling Peptides and Proteins
- Lipopolysaccharide Receptors
(metabolism)
- Lung
(drug effects, immunology, metabolism, pathology)
- Mice
- Mice, 129 Strain
- Mice, Knockout
- Peptides
(deficiency, genetics)
- Pneumonia
(chemically induced, genetics, immunology, metabolism, pathology)
- Proto-Oncogene Proteins c-ets
(metabolism)
- Pulmonary Surfactant-Associated Protein C
- Signal Transduction
- Time Factors
- Toll-Like Receptor 4
(metabolism)
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