Surfactant proteins A and B (SP-A, SP-B) contribute to the metabolism and surface tension reducing properties of pulmonary surfactant phospholipids and are critical for lung function after birth. We have previously demonstrated regulation of SP-A and SP-B expression in the NCI H441, human pulmonary adenocarcinoma cell line. Dexamethasone (dex, 50nM, 24 hrs) inhibited basal expression of SP-A and markedly induced SP-B expression; while tumor necrosis factor alpha (TNF-α) and 12-0-phorbol-13-acetate (TPA) inhibited expression of both SP-A and SP-B mRNA in the H441 cell line. Regulation of these surfactant proteins by dexamethasone, TPA and TNF-α was, at least in part, due to altered mRNA stability.
In order to determine transduction mechanisms by which TPA and TNF-α regulate the surfactant proteins, H441 cells were treated with pentoxifylline(PTX, 100μg/ml) or PDTC (100μM) 2 hrs prior to treatment with TPA or TNF-α. PTX inhibits TNF-α synthesis and cellular activity. PDTC chelates heavy metals and is an antioxidant. PDTC has been utilized as a specific inhibitor of the nuclear transcription factor, NFκB, which mediates effects of TNF-α. Cells to be assayed for SP-B mRNA were pretreated with dex 24 hours prior to PTX/PDTC. PTX, blocked the TNF-α mediated inhibition of SP-A and SP-B mRNA by approximately 80% and did not affect regulation by dex or by TPA. PDTC decreased expression of both SP-A and SP-B mRNA by approximately 75%, with or without pretreatment with dex. PDTC did not inhibit TPA or TNF-α mediated regulation of SP-A and SP-B mRNA. As an internal control, expression of βactin mRNA was not altered by any of the agents tested. These preliminary data support the hypotheses: 1) that PTX effectively blocks effects of TNF-α on pulmonary cells, 2) that inhibition of surfactant proteins by TPA is not mediated by induction of TNF-α and 3) that the expression level of SP-A and SP-B mRNA is dependent on the oxidative status of the H441 cells. Supported by NIH Clinical Investigator Award, 5 K08 HL03318-02.
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(Sponsored by Dale L. Phelps)
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Pryhuber, G., Zhao, Q. PYRROLIDINE DITHIOCARBAMATE (PDTC) INHIBITS SURFACTANT PROTEIN-A AND -B mRNA EXPRESSION IN HUMAN PULMONARY ADENOCARCINOMA CELL LINE. † 2061. Pediatr Res 39 (Suppl 4), 346 (1996). https://doi.org/10.1203/00006450-199604001-02085
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DOI: https://doi.org/10.1203/00006450-199604001-02085