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. 2024 Apr 10;25(8):4184.
doi: 10.3390/ijms25084184.

Maximizing the Therapeutic Effect of Endothelin Receptor Antagonists in Pulmonary Fibrosis: A Paradigm for Treating the Disease

Jerome Cantor  1
Affiliations

Maximizing the Therapeutic Effect of Endothelin Receptor Antagonists in Pulmonary Fibrosis: A Paradigm for Treating the Disease

Jerome Cantor. Int J Mol Sci. .

Abstract

Using a lipopolysaccharide model of acute lung injury, we previously showed that endothelin-1 (ET-1), a potent mediator of vasoconstriction, may act as a "gatekeeper" for the influx of inflammatory cells into the lung. These studies provided a rationale for testing the effect of HJP272, an endothelin receptor antagonist (ERA), in hamster models of pulmonary fibrosis induced by intratracheal instillation of either bleomycin (BLM) or amiodarone (AM). To determine the temporal effects of blocking ET-1 activity, animals were given HJP272 either 1 h before initiation of lung injury or 24 h afterward. The results indicated that pretreatment with this agent caused significant reductions in various inflammatory parameters, whereas post-treatment was ineffective. This finding suggests that ERAs are only effective at a very early stage of pulmonary fibrosis and explains their lack of success in clinical trials involving patients with this disease. Nevertheless, ERAs could serve as prophylactic agents when combined with drugs that may induce pulmonary fibrosis. Furthermore, developing a biomarker for the initial changes in the lung extracellular matrix could increase the efficacy of ERAs and other therapeutic agents in preventing the progression of the disease. While no such biomarker currently exists, we propose the ratio of free to peptide-bound desmosine, a unique crosslink of elastin, as a potential candidate for detecting the earliest modifications in lung microarchitecture associated with pulmonary fibrosis.

Keywords: amiodarone; bleomycin; emergent phenomena; endothelin; endothelin receptor antagonists; lipopolysaccharide; pulmonary fibrosis.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
(A) Hamster lung at three weeks post-instillation of BLM showed inflammatory cell infiltrates and marked interstitial thickening with fibrosis (indicated by arrows). (B) Normal lung for comparison.
Figure 2
Figure 2
(A) Normal hamster lung. (B) Intratracheal instillation of BLM alone induced extensive pulmonary fibrosis. (C) Treatment with HJP272 before BLM significantly decreased fibrosis. (D) Treatment with HJP272 after BLM was much less effective in reducing fibrosis.
Figure 3
Figure 3
Graph showing the level of BLM-induced fibrosis in the various treatment groups, as measured by the fibrotic index.
Figure 4
Figure 4
(A) Hamster lung at three weeks post-instillation of AM showing inflammation and marked interstitial fibrosis. (B) Lung with interstitial fibrosis and alveolar epithelial hyperplasia.
Figure 5
Figure 5
Diagram showing the mechanism of AM-induced pulmonary fibrosis and the pathways where ET-1 may play a role in the fibrotic process.
Figure 6
Figure 6
(A) Normal hamster lung. (B) Intratracheal instillation of AM alone induced extensive pulmonary fibrosis. (C) Treatment with HJP272 before AM markedly reduced fibrosis. (D) Treatment with HJP272 after AM had a minimal effect on fibrosis.
Figure 7
Figure 7
Graph showing the level of AM-induced fibrosis in the various treatment groups, as measured by the fibrotic index.
Figure 8
Figure 8
Fibrogenesis is represented by an increase in K2 (bold) units, which is associated with the redistribution of mechanical forces in the lung.
See this image and copyright information in PMC

References

    1. Hardie W.D., Glasser S.W., Hagood J.S. Emerging concepts in the pathogenesis of lung fibrosis. Am. J. Pathol. 2009;175:3–16. doi: 10.2353/ajpath.2009.081170. - DOI - PMC - PubMed
    1. Lüscher T.F., Barton M. Endothelins and endothelin receptor antagonists: Therapeutic considerations for a novel class of cardiovascular drugs. Circulation. 2000;102:2434–2440. doi: 10.1161/01.CIR.102.19.2434. - DOI - PubMed
    1. Inoue A., Yanagisawa M., Kimura S., Kasuya Y., Miyauchi T., Goto K., Masaki T. The human endothelin family: Three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc. Natl. Acad. Sci. USA. 1989;86:2863–2867. doi: 10.1073/pnas.86.8.2863. - DOI - PMC - PubMed
    1. Yanagisawa M., Kurihara H., Kimura S., Tomobe Y., Kobayashi M., Mitsui Y., Yazaki Y., Goto K., Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411–415. doi: 10.1038/332411a0. - DOI - PubMed
    1. Olgun N., Patel H.J., Stephani R., Wang W., Yen H., Reznik S.E. Effect of the putative novel selective ETA-receptor antagonist HJP272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one, on infection-mediated premature delivery. Can. J. Physiol. Pharmacol. 2008;86:571–575. doi: 10.1139/Y08-057. - DOI - PubMed