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Proinflammatory Cytokines Found in Amniotic Fluid Induce Collagen Remodeling, Apoptosis, and Biophysical Weakening of Cultured Human Fetal Membranes¹

Department of Pediatrics,³ MetroHealth Medical Center (MHMC), Case Western Reserve University (CWRU), Cleveland, Ohio 44109 Department of Reproductive Biology,⁴ MHMC, CWRU, Cleveland, Ohio 44109 Department of Mechanical and Aerospace Engineering,⁵ CWRU, Cleveland, Ohio 44109 Department of Pathology,⁶ University Hospitals of Cleveland and CWRU School of Medicine, Cleveland, Ohio 44109

ABSTRACT

The mechanisms by which fetal membranes (FM) rupture during the birth process are unknown. We have recently reported that FM weaken, at least in part, because of a developmental process of extracellular matrix remodeling and apoptosis. We now hypothesize that cytokines that normally increase in amniotic fluid at term induce FM collagen remodeling and apoptosis with concomitant weakening. Full-thickness FM fragments were cultured with (0–100ng/ml) or without tumor necrosis factor (TNF) or interleukin 1, beta (IL1B). Physical properties were then examined with specially adapted industrial rupture strength testing equipment. Cultured FM were also evaluated for evidence of collagen remodeling and apoptosis. Cytokine-treated FM exhibited a dose-dependent decrease in strength and work to rupture. Compared with controls, the highest TNF dose caused maximal decrease in FM rupture strength (13.2 ± 1.2 N versus 3.8 ± 1.5 N; P = 0.0003) and work to rupture (0.035 ± 0.005 J versus 0.005 ± 0.002 J; P < 0.0001). The highest IL1B dose also decreased rupture strength (12.9 ± 3.2 versus 4.6 ± 1.1 N; P = 0.0027) and work to rupture (0.018 ± 0.005 J versus 0.005 ± 0.002 J; P < 0.01). Matrix metalloproteinase 9 (MMP9) protein increased, tissue inhibitor of matrix metalloproteinase 3 (TIMP3) protein decreased, and poly (ADP-ribose) polymerase (PARP1) cleavage increased with increasing TNF or IL1B doses (all P < 0.05), suggesting collagen remodeling and apoptosis. TNF and IL1B cause significant weakening of cultured FM. Both cytokines induce biochemical markers in the FM in a manner characteristic of the weak zone of FM overlying the cervix. TNF and or IL1B may be involved in the development of the weak zone of the FM.

apoptosis, cytokines, parturition, placenta

¹ Supported by NIH HD39159 and HD48476 to J.J.M.

² Correspondence: John J. Moore, Division of Neonatology, MetroHealth Medical Center, 2500 MetroHealth Dr., Cleveland, OH 44109. FAX: 216 778 3252; jmoore{at}metrohealth.org

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				C. E. Kendal-Wright Stretching, Mechanotransduction, and Proinflammatory Cytokines in the Fetal Membranes Reproductive Sciences, December 1, 2007; 14(8_suppl): 35 - 41. [Abstract] [PDF]

				M. E. Khwad, V. Pandey, B. Stetzer, B. M. Mercer, D. Kumar, R. M. Moore, J. Fox, R. W. Redline, J. M. Mansour, and J. J. Moore Fetal Membranes From Term VAginal Deliveries Have a Zone of Weakness Exhibiting Characteristics of Apoptosis and Remodeling Reproductive Sciences, April 1, 2006; 13(3): 191 - 195. [Abstract] [PDF]