Cyclooxygenase-1–selective inhibition prolongs gestation in mice without adverse effects on the ductus arteriosus
Abstract
Preterm delivery is the leading cause of neonatal mortality and contributes significantly to infant morbidity. Classical cyclooxygenase (COX) inhibitors, such as indomethacin, which inhibit both COX-1 and COX-2, are effective for delaying premature labor, but their use is limited by serious complications to the fetus and neonate, including adverse effects on the ductus arteriosus (DA). Using isoform-selective inhibitors, we characterized the roles of the COX isoforms in the initiation of labor and the regulation of fetal and neonatal DA closure in mice. Chronic inhibition of COX-2 during pregnancy (gestation days 15–18) significantly increased neonatal mortality by preventing closure of the DA after birth, whereas acute COX-2 inhibition near the end of term (gestation day 18) constricted the fetal DA. In contrast, the inhibition of COX-1 during pregnancy lacked these prenatal and postnatal adverse effects on the DA and effectively delayed the initiation of full-term labor and LPS-induced preterm labor. These findings suggest that premature fetal DA closure or neonatal patent DA observed following indomethacin tocolysis in women may result from the inhibition of COX-2. Therefore, COX-1–selective inhibitors may provide effective treatment to delay preterm labor with fewer adverse effects on fetal or neonatal health than nonselective or COX-2–selective inhibitors.
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The prolonged gestation interval observed in the ERKdko females was reminiscent of phenotype described for the cyclooxygenase 1 (PGHS1/COX1) knockout animal.
“First, the prolonged gestation interval observed in the ERKdko females was reminiscent of phenotype described for the cyclooxygenase 1 (PGHS1/COX1) knockout animal34–39.”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [35]
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Cao, J., Nakamura, T., Kitazawa, T., Yamashiki, N., Yamamoto, T., & Taneike, T. (2008) · Prostaglandins & Other Lipid Mediators · doi:10.1016/j.prostaglandins.2008.02.002 · Cited by 6 · see citing works
Asghari-Roodsari, A., Lesani, A., Paydar, M. J., Tabatabaeefar, L., Tavangar, S. M., Norouzi, A., & Dehpour, A. R. (2010) · Reproductive Sciences · doi:10.1177/1933719109358456 · Cited by 6 · see citing works
Inagaki, M., Nishimura, T., Akanuma, S., Nakanishi, T., Tachikawa, M., Tamai, I., Hosoya, K., Nakashima, E., & Tomi, M. (2017) · Placenta · doi:10.1016/j.placenta.2017.04.002 · Cited by 5 · see citing works
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Cardiorenal Physiology of the Mouse: From Loss of Genome to Gain of Phenome
Schnermann, J. B., Lorenz, J. N., & Briggs, J. P. (2008) · Elsevier eBooks · doi:10.1016/b978-1-4160-0252-9.50007-0 · Cited by 1 · see citing works
Recent Advances Concerning the Molecular Mechanism of Patent Ductus Arteriosus
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van der Sterren, S. (2016) · doi:10.26481/dis.20160309ss
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BindingDB Entry 50012431: Synthesis, Inhibitory Activity, and
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- Authors
- Loftin, C. D., Trivedi, D. B., & Langenbach, R.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Langenbach, Robert
- Venue
- Journal of Clinical Investigation
- Published
- 2002-08-15
- Volume
- 110
- Issue
- 4
- Pages
- 549-557
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W4256099920
- Cited by
- 65
- References
- 45
- Citations by year
- 2023: 3 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 1 · 2017: 1 · 2016: 1 · 2014: 1 · 2013: 4 · 2012: 5
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Funders
- Ono Pharmaceutical
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Cardiovascular Conditions and Treatments
- Health Sciences › Medicine › Epidemiology › Preterm Birth and Chorioamnionitis
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Keywords
- cyclooxygenase-1, cyclooxygenase-2, preterm labor, preterm birth, ductus arteriosus closure, tocolysis, indomethacin, isoform-selective inhibitors, labor initiation, neonatal mortality, pregnancy
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