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Javier Arias-Diaz, MD, PhD; Natividad Villa; Jorge Hernández, MD, PhD; Elena Vara, PhD; José L. Balibrea, MD, PhD

Arch Surg. 1997;132(12):1352-1361.

Abstract
Background
An increase in cyclic guanosine 3',5'-monophosphate (cGMP) due to nitric oxide generation is known to participate in the mediation of the tumor necrosis factor (TNF-) effect in type II cells. Because guanylyl cyclase can be activated also by carbon monoxide (CO), in this study we examined the ability of human type II pneumocytes to produce CO in the presence of cytokines and the relative contribution of this molecule to the TNF- and interleukin 1 effects.

Design
Type II pneumocytes were isolated from cadaveric multiple-organ donors by enzymatic digestion, adherence separation of macrophages, and gradient purification. After preculture for 24 hours, cells were cultured for 24 hours in the presence or absence of TNF-, interleukin 1, sodium nitroprusside, Nnitro-L-arginine, CO, hemin, zinc-protoporphyrin type IX, deferoxamine mesylate, S-adenosyl-L-methionine, -tocopherol, methylene blue (a guanylyl cyclase inhibitor), 8-bromine-cGMP, and combinations of these reagents. Both CO (picomole per microgram of protein) and nitric oxide release to the medium and the cGMP (picomole per microgram of protein) content of the cells were measured. In a different set of experiments, D-glucose labeled with radioactive carbon (¹⁴C) was added to the medium, and the labeling of several lipid fractions was determined (picomole per microgram of protein).

Results
D-[¹⁴C]glucose incorporation into phosphatidylcholine, the main surfactant component, was selectively inhibited in the presence of cytokines, CO, sodium nitroprusside, or 8-bromine-cGMP. The inhibitory effect of TNF- was partially reversed by N-nitro-L-arginine, deferoxamine, or -tocopherol and totally reversed by methylene blue. Tumor necrosis factor induced an increase in cGMP cell content and in the CO and nitric oxide release to the medium. Hemin increased CO and cGMP production and decreased phosphatidylcholine synthesis. Zinc-protoporphyrin type IX, an inhibitor of heme oxygenase, and all 3 antioxidants, which inhibited CO production, also antagonized the TNF- effect on cGMP and phosphatidylcholine synthesis.

Conclusions
Intracellular cGMP increase due to an endogenous generation of both CO and nitric oxide mediates the cytokine-induced inhibition of surfactant synthesis by type II pneumocytes. Both lipid peroxidation and heme oxygenase activity are sources for the observed CO production.

Arch Surg. 1997;132:1352-1361

Author Affiliations
From the Department of Surgery, Hospital San Carlos (Drs Arias-Díaz, Hernández, and Balibrea), and the Department of Biochemistry, Facultad de Medicina, Universidad Complutense (Ms Villa and Dr Vara), Madrid, Spain.

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