Pulmonary Foreign-Body Granulomatosis Staloch, Dustin A; Hedley, J. Stephen
The New England journal of medicine,
09/2017, Letnik:
377, Številka:
13
Journal Article
Recenzirano
A 31-year-old woman receiving total parenteral nutrition after small-bowel resection presented with progressive exertional dyspnea. CT and lung biopsy confirmed a diagnosis of pulmonary foreign-body ...granulomatosis due to parenteral injection of oral opiates.
Bone morphogenetic proteins (BMPs) have an anti-fibrogenic function in the kidney, lung, and liver. However, their role in chronic pancreatitis (CP) is unknown. The aim of this study was to define ...the anti-fibrogenic role of BMP signaling in the pancreas in vivo under CP induction. Mice with a deletion of BMP type II receptor (BMPR2(+/-)) were used in this study in comparison with wild-type mice. CP was induced by repetitive cerulein injection intraperitoneally for 4 weeks, and the severity of CP was evaluated. Pancreatic stellate cells (PSCs) were isolated from the mice and treated with BMP2 and TGF-β in vitro, and extracellular matrix protein (ECM) production was measured. Smad and mitogen-activated protein kinase (MAPK) signaling was also evaluated. BMPR2(+/-) mice revealed a greater pancreatic fibrosis, PSC activation and leukocyte infiltration after CP induction compared to wild-type mice (P<0.05). Under CP induction, phospho (p)Smad1/5/8 was elevated in wild-type mice and this effect was abolished in BMPR2(+/-) mice; pSmad2 and pp38(MAPK) were further enhanced in BMPR2(+/-) mice compared to wild-type mice (P<0.05). In vitro, BMP2 inhibited TGF-β-induced ECM protein fibronectin production in wild-type PSCs; this effect was abolished in BMPR2(+/-) PSCs (P<0.05). In BMPR2(+/-) PSCs, pSmad1/5/8 level was barely detectable upon BMP2 stimulation, while pSmad2 level was further enhanced by TGF-β stimulation, compared to wild-type PSCs (P<0.05). BMPR2/Smad1/5/8 signaling plays a protective role against cerulein-induced pancreatic fibrosis by inhibiting Smad2 and p38(MAPK) signaling pathways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epigenetic changes are associated with the regulation of transcription of key cell regulatory genes micro RNAs (miRNAs) during different types of liver injury. This study evaluated the role of ...methylation-associated miRNA, miR-34a, in alcoholic liver diseases. We identified that ethanol feeding for 4 weeks significantly up-regulated 0.8% of known miRNA compared with controls, including miR-34a. Treatment of normal human hepatocytes (N-Heps) and cholangiocytes human intrahepatic biliary epithelial cells (HiBECs) with ethanol and lipopolysaccharide induced a significant increase of miR-34a expression. Overexpression of miR-34a decreased ethanol-induced apoptosis in both N-Heps and HiBECs. In support of the concept that the 5′-promoter region of miR-34a was noted to be embedded within a CpG island, the expression level of miR-34a was significantly increased after demethylation treatment in N-Heps and HiBECs. By methylation-specific PCR, we confirmed that miR-34a activation is associated with ethanol-linked hypomethylation of the miR-34a promoter. A combination of bioinformatics, dual-luciferase reporter assay, mass spectrometry, and Western blot analysis revealed that caspase-2 and sirtuin 1 are the direct targets of miR-34a. Furthermore, modulation of miR-34a also altered expression of matrix metalloproteases 1 and 2, the mediators involved in hepatic remodeling during alcoholic liver fibrosis. These findings provide the basis for an exciting field in which the epigenomic microRNAs of hepatic cells may be manipulated with potential therapeutic benefits in human alcoholic liver diseases.
Cholangiocarcinoma (CCA) is a biliary cancer arising from damaged bile ducts. Epithelial‐mesenchymal transition (EMT) occurs as epithelial cells begin to resemble mesenchymal cells leading to ...increased invasion potential as the extracellular matrix (ECM) degrades. Histamine exerts its effects by way of four receptors (H1‐H4 HRs). Clobenpropit, a potent H4HR agonist, inhibits mammary adenocarcinoma growth. We have shown that (1) cholangiocytes and CCA cells express H1‐H4 HRs and (2) the H3HR decreases CCA proliferation. We evaluated the effects of clobenpropit on CCA proliferation, invasion, EMT phenotypes, and ECM degradation. In vitro, we used CCA cell lines to study proliferation, signaling pathways, and the morphological invasive potential. Gene and protein expression of the hepatobiliary epithelial markers CK‐7, CK‐8, and CK‐19, the focal contact protein paxillin, and the mesenchymal markers fibronectin, s100A4, and vimentin were evaluated. Cell invasion across an ECM layer was quantitated and matrix metalloproteinase‐1, ‐2, ‐3, ‐9, and ‐11 gene and protein expression was examined. Evaluation of the specific role of H4HR was performed by genetic knockdown of the H3HR and overexpression of H4HR. Proliferation was evaluated by proliferating cellular nuclear antigen immunoblotting. In vivo, xenograft tumors were treated with either vehicle or clobenpropit for 39 days. Tumor volume was recorded every other day. Clobenpropit significantly decreased CCA proliferation by way of a Ca2+‐dependent pathway and altered morphological development and invasion. Loss of H3HR expression or overexpression of H4HR significantly decreased CCA proliferation. In vivo, clobenpropit inhibited xenograft tumor growth compared with controls. Conclusion: Modulation of H4HR by clobenpropit disrupts EMT processes, ECM breakdown, and invasion potential and decreases tumor growth. Interruption of tumorigenesis and invasion by histamine may add to therapeutic advances for CCAs. (HEPATOLOGY 2011;)
Functional pluripotent characteristics have been observed in specific subpopulations of hepatic cells that express some of the known cholangiocyte markers. Although evidence indicates that specific ...cytokines, granulocyte macrophage colony‐stimulating factors (GM‐CSFs), and stem cell factors (SCFs) may be candidate treatments for liver injury, the role of these cytokines in intrahepatic biliary epithelium remodeling is unknown. Thus, our aim was to characterize the specific cytokines that regulate the remodeling potentials of cholangiocytes after 70% partial hepatectomy (PH). The expression of the cytokines and their downstream signaling molecules was studied in rats after 70% PH by immunoblotting and in small and large murine cholangiocyte cultures (SMCCs and LMCCs) by immunocytochemistry and real‐time polymerase chain reaction (PCR). There was a significant, stable increase in SCF and GM‐CSF levels until 7 days after PH. Real‐time PCR analysis revealed significant increases of key remodeling molecules, such as S100 calcium‐binding protein A4 (S100A4) and miR‐181b, after SCF plus GM‐CSF administration in SMCCs. SMCCs produced significant amounts of soluble and bound SCFs and GM‐CSFs in response to transforming growth factor‐beta (TGF‐β). When SMCCs were incubated with TGF‐β plus anti‐SCF+GM‐CSF antibodies, there was a significant decrease in S100A4 expression. Furthermore, treatment of SMCCs with SCF+GM‐CSF significantly increased matrix metalloproteinases (MMP‐2 and MMP‐9) messenger RNA as well as miR‐181b expression, along with a reduction of metalloproteinase inhibitor 3. Levels of MMP‐2, MMP‐9, and miR‐181b were also up‐regulated in rat liver and isolated cholangiocytes after PH. Conclusion: Our data suggest that altered expression of SCF+GM‐CSF after PH can contribute to biliary remodeling (e.g., post‐transplantation) by functional deregulation of the activity of key signaling intermediates involved in cell expansion and multipotent differentiation. (HEPATOLOGY 2012;;55:209–221)
: Cardiogenic shock is associated with a mortality rate between 40-60%, and as high as 70% in the setting of ST-elevation myocardial infarction.1-5 In patients with cardiogenic shock, mechanical ...support is often needed for temporary support as a bridge to decision. The Impella 5.0 and 5.5 (Abiomed, Danvers, Massachusetts) micro-axial pumps are left ventricular assist devices (LVAD) that pull blood from the left ventricle into the ascending aorta.6 We sought to describe outcomes and potential complications associated with extended Impella 5.5 and 5.0 in cardiogenic shock.
We retrospectively evaluated patients who underwent implantation of Impella 5.0 and 5.5 in the operating room due to cardiogenic shock between August 1st, 2018 and December 31st, 2020 at our institution. Hemolysis was defined as plasma free hemoglobin level above 50 mg/dL, a lactate dehydrogenase (LDH) level above 500 units/L, and bilirubin increase above 1 mg/dL.
19 patients underwent insertion of Impella 5.0 or 5.5 in the operating room with 14 patients receiving Impella 5.5 and 5 receiving Impella 5.0. Devices were placed in the axillary artery (14), ascending aorta (3), and carotid artery (2). Mean age was 52.6 ± 13.3 years, and most patients (84%) were male. The mean left ventricular ejection fraction (LVEF) was 13.7 ± 6.8%, with 58% of patients with EF 10% or less. The etiology was acute decompensated heart failure in 14 patients and acute myocardial infarction in 5 patients. The average duration of Impella 5.5/5.0 support was 12.5 days (1, 40). Six patients (32%) had the device for more than 14 days. Four patients had Impella CP placed prior to 5.5 for 4.75 days (1,8), and two patients required support with extracorporeal membrane oxygenation (ECMO), both after CP but prior to 5.0. Seven patients (37%) were successfully bridged to either left ventricular assist device (LVAD) or heart transplantation on average of 13 ± 10.8 days after Impella insertion with 43% (6/14) of the 5.5 cohort, and 20% (1/5) of the 5.0 cohort. Overall survival rate was 32% (6/19) with rate of 36% (5/14) for Impella 5.5 and 20% (1/5) for Impella 5.0. Overall hemolysis rate was 47%, with 60% (3/5) in the 5.0 cohort and 43% (6/14) in the 5.5 cohort. Other complications included significant upper extremity neuropathy (1), improper positioning (6), hematoma (3), thrombus (1), and stroke (3).
: There is high mortality associated with cardiogenic shock. The Impella 5.0 and 5.5 can provide additional cardiac support and help with bridging to LVAD or heart transplantation. About a third of the patients were successfully bridged, but serious complications do occur with extended support, including hemolysis, hematoma, thrombus, and stroke. Six patients survived to discharge.
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