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Placental extracellular vesicles-associated miRNA-519c mediates endotoxin adaptation in pregnancy

Tiozzo, Caterina; Bustoros, Mark; Lin, Xinhua; Manzano de Mejia, Claudia; Gurzenda, Ellen; Chavez, Martin; Hanna, Iman; Aguiari, Paola; Perin, Laura; Hanna, Nazeeh
BACKGROUND:Pregnancy represents a unique challenge for the maternal-fetal immune interface, requiring a balance between immunosuppression, which is essential for the maintenance of a semi-allogeneic fetus, and pro-inflammatory host defense to protect the maternal-fetal interface from invading organisms. Adaptation to repeated inflammatory stimuli (endotoxin tolerance) may be critical in preventing inflammation-induced preterm birth resulting from exaggerated maternal inflammatory responses to mild/moderate infections that are common during pregnancy. However, the exact mechanisms contributing to the maintenance of tolerance to repeated infections are not completely understood. miRNAs play important roles in pregnancy, with several miRNAs implicated in gestational tissue function, as well as in pathologic pregnancy conditions. miRNA-519c, a member of the C19MC cluster, is a human-specific miRNA mainly expressed in the placenta. However, its role in pregnancy is largely unknown. OBJECTIVES/OBJECTIVE:To explore the role of "endotoxin tolerance" failure in the pathogenesis of an exaggerated inflammatory response often seen in inflammation-mediated preterm birth. In this study, we investigated the role of miRNA-519c, a placenta-specific miRNA, as a key regulator of endotoxin tolerance at the maternal-fetal interface. STUDY DESIGN/METHODS:-trimester placentas were treated with LPS. After 24 hours, the conditioned media was collected for analysis, and the placental explants were re-exposed to repeated doses of LPS for 3 days. The supernatant was analyzed for inflammatory markers, presence of extracellular vesicles (EVs) and microRNAs. To study the possible mechanism of action of the microRNAs, we evaluated the phosphodiesterase 3 B (PDE3B) pathway involved in TNF-α production using a miRNAs mimic and PDE3B siRNA transfection. Finally, we analyzed human placental samples from different gestational ages and from women affected by inflammation-associated pregnancies. RESULTS:Our data showed that repeated exposure of the human placenta to endotoxin challenges induced a tolerant phenotype characterized by decreased TNF-α and upregulated IL-10 levels. This reaction was mediated by the placenta-specific miRNA-519c packaged within placental EVs. LPS treatment increased the EVs that were positive for the exosome tetraspanin markers, namely CD9, CD63, and CD81, and secreted primarily by trophoblasts. Primary human trophoblast cells transfected with miR-519c mimic decreased PDE3B. While lack of PDE3B, achieved by siRNA transfection, resulted in a decreased TNF-α production. These data supported the hypothesis that the anti-inflammatory action of miRNA-519c was mediated by a downregulation of the phosphodiesterase 3 B pathway, leading to inhibition of TNF-α production. Furthermore, human placentas from normal and inflammation-associated pregnancies demonstrated that decreased placental miRNA-519c level was linked to infection-induced inflammatory pathologies during pregnancy. CONCLUSION/CONCLUSIONS:We identified miRNA-519c, a human placenta-specific miRNA, as a novel regulator of immune adaptation associated with infection-induced preterm birth at the maternal-fetal interface. Our study can serve as a basis for future experiments to explore the potential use of miRNA-519c as a biomarker for infection-induced preterm birth.
PMID: 34181894
ISSN: 1097-6868
CID: 4926282

Underestimation of SARS-CoV-2 infection in placental samples [Letter]

Hanna, Nazeeh; Lin, Xinhua; Thomas, Kristen; Vintzileos, Anthony; Chavez, Martin; Palaia, Thomas; Ragolia, Louis; Verma, Sourabh; Khullar, Poonam; Hanna, Iman
PMID: 34297970
ISSN: 1097-6868
CID: 4954872

Pathological findings in the postmortem liver of patients with coronavirus disease 2019 (COVID-19)

Zhao, Chaohui Lisa; Rapkiewicz, Amy; Maghsoodi-Deerwester, Mona; Gupta, Mala; Cao, Wenqing; Palaia, Thomas; Zhou, Jianhong; Ram, Bebu; Vo, Duc; Rafiee, Behnam; Hossein-Zadeh, Zarrin; Dabiri, Bahram; Hanna, Iman
Although coronavirus disease 2019 (COVID-19) is transmitted via respiratory droplets, there are multiple gastrointestinal and hepatic manifestations of the disease, including abnormal liver-associated enzymes. However, there are not many published articles on the pathological findings in the liver of patients with COVID-19. We collected the clinical data from 17 autopsy cases of patients with COVID-19 including age, sex, Body mass index (BMI), liver function test (alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), alkaline phosphatase (ALP), direct bilirubin, and total bilirubin), D-dimer, and anticoagulation treatment. We examined histopathologic findings in postmortem hepatic tissue, immunohistochemical (IHC) staining with antibody against COVID-19 spike protein, CD68 and CD61, and electron microscopy. We counted the number of megakaryocytes in liver sections from these COVID-19-positive cases. Abnormal liver-associated enzymes were observed in 12 of 17 cases of COVID-19 infection. With the exception of three cases that had not been tested for D-dimer, all 14 patients' D-dimer levels were increased, including the cases that received varied doses of anticoagulation treatment. Microscopically, the major findings were widespread platelet-fibrin microthrombi, steatosis, histiocytic hyperplasia in the portal tract, mild lobular inflammation, ischemic-type hepatic necrosis, and zone 3 hemorrhage. Rare megakaryocytes were found in sinusoids. COVID-19 IHC demonstrates positive staining of the histiocytes in the portal tract. Under electron microscopy, histiocyte proliferation is present in the portal tract containing lipid droplets, lysosomes, dilated ribosomal endoplasmic reticulum, microvesicular bodies, and coronavirus. The characteristic findings in the liver of patients with COVID-19 include numerous amounts of platelet-fibrin microthrombi, as well as various degrees of steatosis and histiocytic hyperplasia in the portal tract. Possible mechanisms are also discussed.
PMID: 33307078
ISSN: 1532-8392
CID: 4770842

Incidental finding of inflammatory fibroid polyp of the appendix in a patient with acute appendicitis

Sy, Alexander M; Vo, Duc; Friedel, David; Grendell, James; Hanna, Iman
PMID: 33361049
ISSN: 2148-5607
CID: 4770942

Cholesterol Crystal Embolization to the Kidney and to a Duodenal Leiomyoma

Sy, Alexander M; Vedula, Jogarao; Hanna, Iman; Halwan, Bhawna; Saitta, Patrick
Cholesterol crystal embolism can be spontaneous or iatrogenic, and it can involve any organ of the gastrointestinal tract, presenting with common gastrointestinal symptoms such as bleeding, perforation, obstruction, and inflammation. It is therefore considered the "great masquerader," requiring a high level of suspicion because the condition is associated with increased morbidity and mortality. We present a 69-year-old man who presented with gastrointestinal bleeding and azotemia. He was found to have cholesterol crystal embolization in the kidney and a duodenal leiomyoma, the latter being an uncommon site to embolize.
PMID: 30214911
ISSN: 2326-3253
CID: 3659032

An Unusual Place to Land! Cholesterol Crystal Embolization to the Kidney and Duodenal Leiomyoma [Meeting Abstract]

Sy, Alexander; Vedula, Jogarao; Hanna, Iman; Halwan, Bhawna; Saitta, Patrick
ISSN: 0002-9270
CID: 3508522

Sporadic ganglioneuromatosis of esophagogastric junction in a patient with gastro-esophageal reflux disorder and intestinal metaplasia [Case Report]

Siderits, Richard; Hanna, Iman; Baig, Zahid; Godyn, Janusz-J
A 58-year-old female with a recurrent history of upper abdominal pain and intermittent dysphagia underwent endoscopic evaluation that demonstrated an irregular and nodular esophago-gastric (EG) junction and grade I erosive esophagitis. Biopsies showed prominent intestinal metaplasia of Barrett's type without dysplasia, chronic inflammation and multiple aggregates of large cells within the mucosal lamina propria, some with spindle shaped nuclei. Immunohistochemistry stains for keratins AE-1/AE-3 were negative, while S-100 and NSE were positive. This, together with routine stains, was diagnostic for mucosal ganglioneuromatosis. The background of chronic inflammation with intestinal type metaplasia was consistent with long-term reflux esophagitis. No evidence of achalasia was seen. Biopsies of gastric antrum and fundus were unremarkable, without ganglioneural proliferation. Colonoscopy was unremarkable. No genetic syndromes were identified in the patient including familial adenomatous polyposis and multiple endocrine neoplasia type IIb (MEN IIb). Iansoprazole (Prevacid) was started by oral administration each day with partial relief of symptoms. Subsequent esophagogastroscopy repeated at 4 mo showed normal appearing EG junction. Esophageal manometry revealed a mild non-specific lower esophageal motility disorder. Mild motor dysfunction is seen with gastro-esophageal reflux disease (GERD) and we feel that the demonstration of localized ganglioneuromatosis was not likely related etiologically. In the absence of findings that might suggest neural hypertrophy, such as achalasia, the nodular mucosal irregularity seen with this instance of ganglioneuromatosis may, however, have exacerbated the patient's reflux.
PMID: 17203537
ISSN: 1007-9327
CID: 1781072

IFN-gamma-mediated inhibition of COX-2 expression in the placenta from term and preterm labor pregnancies

Hanna, Nazeeh; Bonifacio, Lea; Reddy, Pradeep; Hanna, Iman; Weinberger, Barry; Murphy, Shaun; Laskin, Debra; Sharma, Surendra
PROBLEM: The inflammatory-anti-inflammatory cytokine network is thought to play a critical role in regulated progression and termination of pregnancy. The aim of this study was to evaluate the effects of interferon (IFN)-gamma on the expression of Cyclooxygenase (COX)-2 and production of prostaglandin E(2) (PGE(2)) in the human placenta from term and preterm labor deliveries. METHOD OF STUDY: Placental explant culture system was used. COX-2 expression was determined by complementary techniques of immunohistochemistry and Western blotting. Released IFN-gamma and PGE(2) by placental explants were measured by enzyme-linked immunosorbent assay. Signal transducer and activator of transcription 1 (STAT1) phosphorylation was evaluated by Western blotting using a specific antibody. RESULTS: IFN-gamma was poorly detected in the placenta but was significantly expressed in decidual tissues from both term and preterm pregnancies as detected by immunohistochemistry. IFN-gamma significantly inhibited COX-2 expression and PGE(2) release in cultured placental explants from term and preterm labor deliveries. This effect most likely occurred in a STAT1-dependent manner as this regulatory protein was phosphorylated in response to IFN-gamma. IFN-gamma receptor (IFN-gammaR) was expressed in normal early pregnancy placental samples. However, its expression was significantly reduced in placental samples from term and preterm deliveries. Of interest, IFN-gammaR was expressed in placentas from term and preterm labor deliveries after 24 hr in culture. CONCLUSIONS: Our data suggest that the human placenta is an important site for IFN-gamma-mediated repression of COX-2 expression and PGE2 production, implying that functional withdrawal of IFN-gamma may be involved in the onset of term or preterm labor.
PMID: 15212685
ISSN: 1046-7408
CID: 1781092

Gestational age-dependent expression of IL-10 and its receptor in human placental tissues and isolated cytotrophoblasts

Hanna, N; Hanna, I; Hleb, M; Wagner, E; Dougherty, J; Balkundi, D; Padbury, J; Sharma, S
Control of antifetal immune responses is thought to be regulated locally by the placenta. Because the physiologic programming of the placenta across gestation is likely to influence the local immunity, we hypothesize that a potent anti-inflammatory cytokine such as IL-10 may be produced in a gestational age-dependent manner. In the present study, we examined the expression of IL-10 and its receptor in placental explants or freshly isolated cytotrophoblasts from different gestational ages and compared it with the expression profiles of other cytokines. First and second trimester placental tissues from normal pregnancies predominantly expressed IL-10, whereas the levels of IL-2, IL-4, and IFN-gamma were mostly below detection throughout pregnancy. The expression of IL-10, but not its receptor, diminished significantly in term placental tissues collected "before" the onset of labor and did not change appreciably "after" labor. On the other hand, TNF-alpha and IL-1beta were significantly up-regulated in response to labor-associated conditions. IL-10 expression was transcriptionally attenuated at term as observed in cytotrophoblasts. In contrast to the placental cytokine milieu, autologous PBMCs, when activated with PHA, secreted significant amounts of IL-2, IL-4, IL-10, and IFN-gamma, albeit with a statistically significantly enhanced IL-10 production in first trimester compared with age-matched nonpregnant women. These data suggest that IL-10 is expressed in the placenta in a gestational age-dependent manner and that its down-regulation at term may be an important mechanism underlying the subtle changes associated with parturition.
PMID: 10820249
ISSN: 0022-1767
CID: 3568912