Disease relevance of Sftpc

• To test the hypothesis that NFI isoforms interact with TTF-1 to differentially regulate SP-C transcription, we performed transient transfection assays in JEG-3 cells, a choriocarcinoma cell line with negligible endogenous NFI or TTF-1 activity [1].
• Absence of SP-C caused a severe progressive pulmonary disorder with histologic features consistent with interstitial pneumonitis [2].
• SP-C-deficient (SP-C -/-) mice developed a severe pulmonary disorder associated with emphysema, monocytic infiltrates, epithelial cell dysplasia, and atypical accumulations of intracellular lipids in type II epithelial cells and alveolar macrophages [2].
• Thus, SP-C functions to limit lung inflammation, inhibit collagen accumulation, and restore normal lung structure after bleomycin [3].
• Recent reports have linked mutations in the surfactant protein C gene (SFTPC) to familial forms of pulmonary fibrosis, but it is uncertain whether deficiency of mature SP-C contributes to disease pathogenesis [3].

High impact information on Sftpc

• The A/Japan/57 influenza hemagglutinin (HA) was expressed in BALB/c mice under the transcriptional control of the surfactant protein C (SP-C) promoter, resulting in expression of HA in type II alveolar epithelial cells, as well as low level variable expression in other tissues, including the thymus in some of the founder lines [4].
• Pulmonary pathology in the SP-C TNF-alpha mice bears a striking resemblance to human idiopathic pulmonary fibrosis, in which increased expression of TNF-alpha in type II epithelial cells has also been noted [5].
• Surfactant protein C (SP-C; Sftpc) gene expression is restricted to pulmonary type II epithelial cells [1].
• Overexpression of NmycEGFP in the epithelium under the control of surfactant protein C (Sftpc) regulatory elements expands the domain of S phase cells and upregulates numerous genes associated with growth and metabolism, as shown by transcriptional microarray [6].
• TTF1 expression is unaltered in chimeric lungs whereas SPC and CC10 expression are attenuated in abnormally branched areas of chimeric lungs [7].

Chemical compound and disease context of Sftpc

• In this study, we evaluated bleomycin-induced lung fibrosis in mice with genetic deletion of SFTPC [3].
• The lipopolysaccharide-binding capacity of SP-C is resistant to peroxynitrite, a known mediator of acute lung injury formed by reaction of nitric oxide with superoxide anions [8].
• The effects of n-acetyl cysteine (NAC), s-allyl cysteine (SAC), s-ethyl cysteine, s-methyl cysteine and s-propyl cysteine (SPC) activity on Balb/cA mice against diabetic complications were examined [9].

Biological context of Sftpc

• The morphology of the lungs from SP-C/HFH-4 embryos (day 18 postconception) was distinctly abnormal, and the severity of the alterations correlated with the level of transgene expression as detected by in situ hybridization [10].
• In order to test whether the temporospatial expression of HFH-4 influences lung morphogenesis, HFH-4 was expressed in lungs of transgenic mice under control of the surfactant protein C (SP-C) promoter [10].
• Transgenic mice bearing a chimeric gene composed of the 5'-flanking and promoter regions of the human SP-C gene and the bacterial chloramphenicol acetyltransferase reporter gene were generated, demonstrating that lung-specific and developmental expression was conferred by these 5'-sequences [11].
• Deletion analysis of the SP-C promoter region demonstrated that TNF-alpha inhibited gene expression in constructs containing 320 base pairs 5' from the start of transcription of the mouse SP-C gene [12].
• The gene is composed of six exons and five introns, and its structure is closely related to the human SP-C gene [11].

Anatomical context of Sftpc

• Furthermore, smooth muscle alpha-actin expression was observed surrounding the distal airways of SP-C/gremlin mice, indicating a proximalization of distal lung tubules [13].
• At 3 and 6 weeks after bleomycin, lungs from SFTPC-/- mice had increased fibroblast numbers, augmented collagen accumulation, and greater parenchymal distortion [3].
• Compared with wild-type (SFTPC+/+) controls, mice lacking surfactant protein C (SFTPC-/-) had greater lung neutrophil influx at 1 week after intratracheal bleomycin, greater weight loss during the first 2 weeks, and increased mortality [3].
• In order to determine the mechanism(s) that regulate gene transcription, we have analyzed the activation of the murine SP-C promoter in mouse lung epithelial cells (MLE cells) and in HeLa cells after co-transfection with a vector expressing rat thyroid transcription factor-1 (TTF-1) [14].
• Transcriptional elements from the human SP-C gene direct expression in the primordial respiratory epithelium of transgenic mice [15].

Associations of Sftpc with chemical compounds

• Induction of NFIen in a subset of type II cells inhibited SP-C gene expression without affecting expression of TTF-1 in doxycycline-treated double-transgenic mice [1].
• We found recently that the hydrophobic lung surfactant protein SP-C specifically binds to the lipid A region of lipopolysaccharide (LPS) [16].
• The effects of HIMF on SP-B and SP-C transcription activity, and on mRNA degradation, were investigated in mouse lung epithelial (MLE)-12 and C10 cells using the promoter-luciferase reporter assay and actinomycin D incubation [17].
• We found that among the different hydrophobic components of mouse surfactant separated by gel filtration or reverse-phase HPLC, only SP-C exhibited the capacity to bind to a tritium-labeled LPS [18].
• The LY294002 and wortmannin treatments showed decreased expression of SPC [19].

Regulatory relationships of Sftpc

• In vitro, Sox17 inhibited Sftpc and enhanced Foxj1 promoter activity, consistent with its expression in proximal airway cells [20].
• Tracheal epithelium treated with FGF10 showed little growth and failed to express SP-C as measured by whole-mount in situ hybridization and quantitative real-time polymerase chain reaction [21].
• Transgenic mice expressing Gata6 cDNA under the control of the human Surfactant Protein-C (SP-C) promoter were generated and their lungs were analyzed during fetal stages [22].
• Genetically decreased levels of SP-B combined with superimposed O(2)-induced injury reveals the distinct contribution of SP-C to pulmonary function in vivo [23].

Other interactions of Sftpc

• In situ hybridization with riboprobes for the proximal airway marker, CC10, and the distal airway marker, SP-C, shows normal differentiation of bronchiolar Clara cells but a reduction in the number of differentiated Type II cells in transgenic lungs [24].
• Atypical cuboidal or columnar cells lined the lung periphery of SP-C/HFH-4 transgenic mice [10].
• SP-B and SP-C, but not SP-A, localized predominantly to the glycogen stores [25].
• SP-C/gremlin transgenic mice exhibited a disruption of the proximal-distal patterning found in the airways of the mammalian lung [13].
• FGF-10 induces SP-C and Bmp4 and regulates proximal-distal patterning in embryonic tracheal epithelium [26].

Analytical, diagnostic and therapeutic context of Sftpc

• The temporal-spatial expression of HIMF, SP-B, and SP-C in developing mouse lungs was examined by immunohistochemical staining, Western blot, and RT-PCR [17].
• Data presented here demonstrate that such fetal lung morphogenetic cues induce MESC derivatives to incorporate into the reforming pseudoglandular-like tubular ducts, display pan-keratin and surfactant protein C (Sftpc) immunoreactivity, and express Sftpc transcripts while displaying a normal diploid karyotype in coculture [27].
• The SP-C minimal promoter was found to contain two potential Ets binding sites, and electrophoretic mobility shift assays showed that two 20-bp wild-type oligonucleotides containing the 5'-GGA(A/T)-3' Ets consensus binding motif were shifted by nuclear extracts from MLE15 cells [28].
• Immunocytochemistry showed that with T(3) treatment, Nkx2.1 and surfactant protein SP-C proteins became progressively localized to cuboidal epithelial cells and mesenchymal expression of Hoxb5 was reduced, a pattern resembling late fetal lung development [29].
• Decreased SP-B was associated with low alveolar content of phosphatidylglycerol, accumulation of misprocessed SP-C proprotein in the air spaces, increased protein content in bronchoalveolar lavage fluid, and altered surfactant activity in vitro [30].

References