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December 1995

Both Prostaglandin E2 and Nitric Oxide Sequentially Mediate the Tumor Necrosis Factor α–Induced Inhibition of Surfactant Synthesis by Human Type II Pneumocytes

Author Affiliations

From the Departments of Biochemistry (Facultad de Medicina) (Drs Vara and García) and Surgery (Hospital San Carlos) (Drs Arias-Díaz, Hernández, and Balibrea), Universidad Complutense, Madrid, Spain.

Arch Surg. 1995;130(12):1279-1286. doi:10.1001/archsurg.1995.01430120033005

Background:  Tumor necrosis factor α (TNF-α)—induced inhibition of surfactant synthesis seems to participate in the pathogenesis of the adult respiratory distress syndrome.

Objectives:  To examine the ability of human type II pneumocytes to produce nitric oxide (NO) in the presence of TNF-α and, in addition, to explore the role of this radical in the transduction of the cytokine signal. Design: Multiple organ donors were the source of lung tissue specimens. Type II pneumocytes were isolated by enzymatic digestion, adherence separation of macrophages, and gradient purification. After 24-hour preculture, cells were cultured for 24 hours in the presence or absence of TNF-α (100 ng/mL), sodium nitroprusside (100 μmol/L), Nω-nitro-L-arginine methyl ester (NAME) (1 mmol/L), methylene blue (10 μmol/L), 8-bromo-3',5'-cyclic guanosine monophosphate (8-Br-cGMP) (1 mmol/L), prostaglandin E2 (PGE2) (0.1 μmol/L), indomethacin (30 μmol/L), and combinations. The NO release to the medium and cGMP and PGE2 contents of the cells were measured.

Results:  The incorporation of14C-labeled glucose (D-[U-14C] glucose) into phosphatidylcholine and phosphatidylglycerol was selectively inhibited either by 8-Br-cGMP or in the presence of TNF-α, PGE2, or nitroprusside, all of which caused an increase in the intracellular levels of cGMP. The inhibitory effect of TNF-α was partially reverted by indomethacin, NAME, N-monomethyl arginine, or methylene blue. The inhibitory effect of PGE2 was partially reverted by NAME, while that of nitroprusside was reverted by methylene blue, but not by indomethacin. Tumor necrosis factor α induced an increase in PGE2 (4.31±0.27 vs 1.65±0.17-pg/μg protein, n=10, P<.01) and cGMP (0.238±0.012 vs 0.109±0.014-pmol/μg protein, n=10, P<.01) cell content and in the NO release to the medium (3.10±0.14 vs 1.19±0.11-nmol/μg protein, n=10, P<.01). The basal NO release to the medium was also increased in the presence of PGE2. The NAME, which blocked NO generation and cGMP increase, did not affect PGE2 production in response to TNF-α. However, indomethacin, which blocked PGE2 production, also blunted NO generation and cGMP increase.

Conclusions:  The NO generation, secondary to PGE2 production, seems responsible for the TNF-α–induced inhibition of phosphatidylcholine synthesis by human type II pneumocytes. Nitric oxide seems to exert this effect through activation of guanylyl cyclase.(Arch Surg. 1995;130:1279-1286)

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