Pneumonitis and Emphysema in sp-C Gene Targeted Mice

Glasser, Stephan W.; Detmer, Emily A.; Ikegami, Machiko; Na, Cheng-Lun; Stahlman, Mildred T.; Whitsett, Jeffrey A.

doi:10.1074/jbc.m210909200

Cited by 202 publications

(179 citation statements)

References 32 publications

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“…17,30 -36 SFTPCϪ/Ϫ mice bred into a congenic 129/SV background develop progressive pulmonary disease with parenchymal remodeling, airspace enlargement, and altered pulmonary mechanics. 30 In contrast, SP-C-deficient mice used in our studies (outbred Black Swiss background) show no evidence of lung inflammation or structural abnormalities. However, when combined with partial SP-B deficiency, SFTPCϪ/Ϫ mice (Black Swiss background) developed increased levels of interleukin-6 and interleukin-1␤ in bronchoalveolar lavage and a more severe impairment of pulmonary function than wild-type mice after exposure to hyperoxia.…”

Section: Discussioncontrasting

confidence: 40%

Increased and Prolonged Pulmonary Fibrosis in Surfactant Protein C-Deficient Mice Following Intratracheal Bleomycin

Lawson

Polosukhin

Stathopoulos

et al. 2005

The American Journal of Pathology

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124

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Section: Discussioncontrasting

confidence: 40%

Increased and Prolonged Pulmonary Fibrosis in Surfactant Protein C-Deficient Mice Following Intratracheal Bleomycin

Lawson

Polosukhin

Stathopoulos

et al. 2005

The American Journal of Pathology

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150

124

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“…A complete pulmonary phenotype of this model has not been described. Any mistrafficking of proSP-C due to Nedd4-2 deficiency resulting in selective SP-C deficiency may not be phenotypically dominant as the SP-C null mouse survives to adulthood (45,46) due to redundancy in the biophysical activity provided by surfactant protein B. However, a preliminary report of a second independent Nedd4-2-deficient mouse indicated that perinatal lethality secondary to respiratory insufficiency can occur (47).…”

Section: Discussionmentioning

confidence: 99%

Anterograde Transport of Surfactant Protein C Proprotein to Distal Processing Compartments Requires PPDY-mediated Association with Nedd4 Ubiquitin Ligases

Kotorashvili

Russo

Mulugeta

et al. 2009

Journal of Biological Chemistry

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Biosynthesis of surfactant protein C (SP-C) by alveolar type 2 cells requires proteolytic processing of a 21-kDa propeptide (proSP-C 21 ) in post-Golgi compartments to yield a 3.7-kDa mature form. Scanning alanine mutagenesis, binding assays, and co-immunoprecipitation were used to characterize the proSP-C targeting domain. Delivery of proSP-C 21 to distal processing organelles is dependent upon the NH 2 -terminal cytoplasmic SP-C propeptide, which contains a conserved PPDY motif. In A549 cells, transfection of EGFP/proSP-C 21 constructs containing polyalanine substitution for Glu 11 -Thr 18 , 13 PPDY 16 , or 14 P, 16 Y produced endoplasmic reticulum retention of the fusion proteins. Protein-protein interactions of proSP-C with known WW domains were screened using a solid-phase array that revealed binding of the proSP-C NH 2 terminus to several WW domains found in the Nedd4 family of E3 ligases. Specificity of the interaction was confirmed by co-immunoprecipitation of proSP-C and Nedd4 or Nedd4-2 in epithelial cell lines. By Western blotting and reverse transcription-PCR, both forms were detected in primary human type 2 cells. Knockdown of Nedd4-2 by small interference RNA transfection of cultured human type 2 cells blocked processing of 35 S-labeled proSP-C 21. Mutagenesis of potential acceptor sites for ubiquitination in the cytosolic domain of proSP-C (Lys 6 , Lys 34 , or both) failed to inhibit trafficking of EGFP/proSP-C 21 . These results indicate that PPDYmediated interaction with Nedd4 E3-ligases is required for trafficking of proSP-C. We speculate that the Nedd4/proSP-C tandem is part of a larger protein complex containing a ubiquitinated component that further directs its transport. Surfactant protein C (SP-C)3 is a hydrophobic lung-specific protein that co-isolates with the biophysically active phospholipid fraction of pulmonary surfactant (1). The 3.7-kDa alveolar form of SP-C (SP-C 3.7 or mature SP-C) is a 35-amino acid, valine-rich peptide that results from synthesis of a 197 amino acid precursor form (proSP-C 21 ). Within the endoplasmic reticulum (ER), proSP-C 21 exists as a type II bitopic transmembrane protein (N cyt /C lumen ), which remains integrally membrane-associated while it is extensively processed by four post-translational endoproteolytic cleavages that take place in post-Golgi compartments (2-6). The resulting mature protein is transferred into the lumen of lamellar bodies for secretion into the alveolar space together with surfactant phospholipid and SP-B (7). Thus, the complete biosynthesis of SP-C 3.7 is critically dependent upon oligomeric sorting and targeting of proSP-C 21 to subcellular processing compartments distal to the ER/Golgi.Using deletional mutagenesis, we had previously shown that the NH 2 -terminal propeptide flanking domain (NTP) of proSP-C, which is oriented into the cytosol, contained potential targeting motifs for post-Golgi trafficking (8, 9). The candidate region included the amino acid sequence Met 10 -Thr 18 and, when present, was sufficient to direct transf...

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“…Approximately 90% of surfactant consists of saturated phospholipids, of which phosphatidylcholine is by far the most abundant component with some triacylglycerols and cholesterol, and 10% of lung-specific surfactant proteins (SPs), SP-A, SP-B, SP-C and SP-D 10 . Surfactant deficiency or disruption of production of SPs results in alveolar damage 11,12 . A variety of mutations in the SP-C gene have been identified in patients with pulmonary fibrosis 13,14 .…”

mentioning

confidence: 99%

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

et al. 2013

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Despite the established role of alveolar type II epithelial cells for the maintenance of pulmonary function, little is known about the deregulation of lipid composition in the pathogenesis of pulmonary fibrosis. The elongation of long-chain fatty acids family member 6 (Elovl6) is a rate-limiting enzyme catalysing the elongation of saturated and monounsaturated fatty acids. Here we show that Elovl6 expression is significantly downregulated after an intratracheal instillation of bleomycin (BLM) and in human lung with idiopathic pulmonary fibrosis. Elovl6-deficient (Elovl6 À / À ) mice treated with BLM exhibit severe fibroproliferative response and derangement of fatty acid profile compared with wild-type mice. Furthermore, Elovl6 knockdown induces a change in fatty acid composition similar to that in Elovl6 À / À mice, resulting in induction of apoptosis, TGF-b1 expression and reactive oxygen species generation. Our findings demonstrate a previously unappreciated role for Elovl6 in the regulation of lung homeostasis, and in pathogenesis and exacerbation of BLM-induced pulmonary fibrosis.

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Pneumonitis and Emphysema in sp-C Gene Targeted Mice

Abstract: SP-C-deficient (SP-C

Cited by 202 publications

References 32 publications

Increased and Prolonged Pulmonary Fibrosis in Surfactant Protein C-Deficient Mice Following Intratracheal Bleomycin

Increased and Prolonged Pulmonary Fibrosis in Surfactant Protein C-Deficient Mice Following Intratracheal Bleomycin

Anterograde Transport of Surfactant Protein C Proprotein to Distal Processing Compartments Requires PPDY-mediated Association with Nedd4 Ubiquitin Ligases

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

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