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

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), N^ω-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)