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Expression of Endothelial Nitric Oxide Synthase, Inducible Nitric Oxide Synthase, and Endothelin-1 in Lungs of Subjects Who Died With ARDS^*

^* From the University of Utah, Salt Lake City, UT. Supported by NIH SCOR grant P50 HL50153.

Correspondence to: K. H. Albertine, PhD, University of Utah School of Medicine, 50 N Medical Dr, Room 2A129, Salt Lake City, UT 84132-1001

Persistent pulmonary inflammation and pulmonary hypertension are characteristics of subjects with ARDS. Among the contributing factors to the pathophysiology of ARDS, two enzymes and a peptide are of particular interest: endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and endothelin-1 (ET-1). It is unclear which cells in the lungs of ARDS subjects express these mediators, or how their pattern of expression compares to expression in the lungs of subjects who have nonpulmonary disease. To this end, we performed quantitative immunohistochemistry for eNOS, iNOS, and ET-1 in lung tissue obtained from six subjects who died with ARDS and six subjects who died without ARDS. We used monoclonal antibodies, antigen-retrieval immunoperoxidase methods (with relevant controls), and light microscopic densitometry to compare the distribution of each mediator between the two groups. For light microscopic densitometry, five random fields each were drawn across pulmonary arterial endothelial and smooth muscle cells, airway epithelial cells, and alveolar macrophages. Nuclei were excluded. The image analysis system automatically determined the brown immunostain density. This procedure was repeated for at least 10 vessels, airways, and alveolar macrophages per subject.

The eNOS immunostaining of pulmonary arterial endothelial cells was consistently less in the subjects who died with ARDS (relative densitometry units of 21 ± 7; mean ± SD) compared to subjects who died without ARDS (59 ± 10). We saw little immunostaining of alveolar wall microvessels. The ARDS subjects also consistently had less immunostaining for eNOS in airway epithelial cells (16 ± 7) compared to subjects without ARDS (29 ± 9). Immunostaining for iNOS was restricted to alveolar macrophages (79 ± 11) and airway epithelial cells (31 ± 10) in subjects who died with ARDS. In subjects without ARDS, alveolar macrophages and airway epithelial cells expressed very little iNOS (9 ± 3 and 8 ± 4, respectively). ET-1 expression was observed in vascular endothelial cells (64 ± 8) and smooth muscle cells (25 ± 11), airway epithelial cells (19 ± 7), distal airspace epithelial cells (21 ± 5), and alveolar macrophages (52 ± 6) of subjects with ARDS. Their airspace contents, including hyaline membranes, were ET-1 immunopositive. In contrast, subjects who died without ARDS had very little ET-1 expression (< 10 densitometry units among the cell types).

These results provide cellular identification of the sources of eNOS, iNOS, and ET-1 in the lungs of subjects who died with ARDS, as well as demonstrating striking differences in the phenotypic expression patterns of these inflammatory mediators compared to subjects who died without ARDS.

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This Article Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Albertine, K. H. Articles by Michael, J. R. Search for Related Content PubMed PubMed Citation Articles by Albertine, K. H. Articles by Michael, J. R.