Possible Role of α1-Antitrypsin in Endometriosis-Like Grafts From a Mouse Model of Endometriosis

Abstract

Previous study indicated that bleeding into the peritoneum may accelerate inflammatory response in endometriosis-like grafts in mice. To identify changes in protein levels in the grafts from mice that underwent unilateral ovariectomy (uOVX), which causes bleeding from ovarian arteries and vein, the grafts were generated by injecting a suspension of human endometrial cells in BALB/c nude female mice, and protein profile changes were compared with non-uOVX control mice. The level of α1-antitrypsin (α1-AT) decreased in grafts from nude mice that underwent uOVX. The levels of phosphorylated Akt, mammalian target of rapamycin, S6K, regulatory factors for cell survival, and of phosphorylated nuclear factor κB, an inflammatory mediator, were higher in endometriosis-like grafts from the uOVX group than from the control. The grafts were mostly comprised of stromal cells. The bioactivity of α1-AT was assessed by investigating cytokine expression in protease-activated receptor (PAR) 1/2 agonists-stimulated stromal cells. The PARs promoted the expression of interleukin 8 (IL-8), but treatment with α1-AT blocked IL-8 expression dose dependently. Knocking down α1-AT expression increased the constitutive IL-6, IL-8, and cyclooxygenase 2 expression as well as PAR1 agonist-stimulated IL-6 expression. These findings support the notion that decreased α1-AT protein in the grafts constituted with human endometrial cells in mice may have exacerbated inflammation in endometriosis-like grafts, suggesting the possible involvement of α1-AT in the pathophysiology of endometriosis.

Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells

“…Sustained activation of ERK1/2 was also found to be involved in renal endothelial inflammation [ 42 ], myofibroblast differentiation, extracellular matrix production [ 43 ] and fibrosis [ 44 ] in the course of SSc. Interplay between PAR-1 and p70S6K was also demonstrated in animal models of neuronal ischemia [ 45 ] and endometriosis [ 46 ]. Corroborating our results, phosphorylation of p70S6K was also detected in the renal endothelium of patients with SRC [ 47 ].…”

Point Mutation of a Non-Elastase-Binding Site in Human α1-Antitrypsin Alters Its Anti-Inflammatory Properties

“…As such, it has been proposed that the globular surface of hAAT may contain significant functional attributes. Indeed, it has been established that hAAT directly binds IL-8 ( 21 , 22 ), as well as to polymeric immunoglobulin receptor ( 23 ), gp96 ( 24 ), HSP70 ( 25 ), oxidized cholesterol within lipid rafts and serum lipids ( 26 – 29 ), HDL particles ( 30 – 32 ), and LRP1 receptor ( 33 ). Furthermore, certain activities that are attributed to hAAT appear to be reproducible in formulations that lack elastase inhibition as in the case of recombinant Fc-hAAT and truncated hAAT ( 26 , 34 – 36 ).…”

Alpha-1 Antitrypsin-Induced Endoplasmic Reticulum Stress Promotes Invasion by Extravillous Trophoblasts

“…In human placental tissue, A1AT may interact directly with HTRA1 [4,7] and suppress the inflammatory response [4,7]. The effect of A1AT knockdown (KD) or overexpression (OE) on the expression of HTRAs and the pro-inflammatory genes IL6 and CXCL8 was determined in HTR8/SVneo cells (Figure 1a,b).…”

“…This serine protease inhibitor is present at high circulating concentrations in inflammatory diseases [3]. Previous studies have shown that a reduction of A1AT protein in endometriosis-like lesions exacerbates the inflammatory response in mice [4]. It has been shown that urinary A1AT may represent a marker of the severity of PE [5].…”