CCAAT/enhancer-binding protein δ facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner
Abstract:The authors note that on page 13064, right column, first full paragraph, lines 4-7, "Some of the climatic events linked to such concerns are the severe droughts experienced by the Amazon basin in 2005 and 2010, which reportedly reduced tropical forest NPP by 1.6 to 2.2 PgC/y and increased tree mortality (50, 51)" should instead appear as "Some of the climatic events linked to such concerns are the severe droughts experienced by the Amazon basin in 2005 and 2010, which reportedly reduced tropical forest NPP and… Show more
“…Pictures of collagen staining were taken to cover the entirety of all sections. Colour intensity of stained areas was analysed semi-quantitatively with ImageJ and expressed as percentage of the surface area essentially as described before 24 25. For details, see the online supplementary method section.…”
“…Pictures of collagen staining were taken to cover the entirety of all sections. Colour intensity of stained areas was analysed semi-quantitatively with ImageJ and expressed as percentage of the surface area essentially as described before 24 25. For details, see the online supplementary method section.…”
“…This corroborates other studies that showed an increase of PAFR in the onset of different diseases, like systemic infection, necrotizing enterocolitis, graft-vs-host disease and peripheral nerve injury. [23][24][25][26] As expected, initially, the infiltrating immune cells must be responsible for PAFR expression upregulation, and at later time points the renal cells are also responsible for the maintenance of higher PAFR expression. PAF and a wide range of oxidatively modified phospholipids are recognized by PAFR that is constitutively expressed by cells participating in innate immunity.…”
Platelet-activating factor (PAF) is a lipid mediator with important pro-inflammatory effects, being synthesized by several cell types including kidney cells. Although there is evidence of its involvement in acute renal dysfunction, its role in progressive kidney injury is not completely known. In the present study, we investigated the role of PAF receptor (PAFR) in an experimental model of chronic renal disease. Wild-type (WT) and PAFR knockout (KO) mice underwent unilateral ureter obstruction (UUO), and at kill time, urine and kidney tissue was collected. PAFR KO animals compared with WT mice present: (a) less renal dysfunction, evaluated by urine protein/creatinine ratio; (b) less fibrosis evaluated by collagen deposition, type I collagen, Lysyl Oxidase-1 (LOX-1) and transforming growth factor b (TGF-b) gene expression, and higher expression of bone morphogenetic protein 7 (BMP-7) (3.3-fold lower TGF-b/BMP-7 ratio); (c) downregulation of extracellular matrix (ECM) and adhesion molecule-related machinery genes; and (d) lower levels of pro-inflammatory cytokines. These indicate that PAFR engagement by PAF or PAF-like molecules generated during UUO potentiates renal dysfunction and fibrosis and might promote epithelial-to-mesenchymal transition (EMT). Also, early blockade of PAFR after UUO leads to a protective effect, with less fibrosis deposition. In conclusion, PAFR signaling contributes to a pro-inflammatory environment in the model of obstructive nephropathy, favoring the fibrotic process, which lately will generate renal dysfunction and progressive organ failure.
“…(immuno)histochemistry Histological examination was performed essentially as previously described (29,30). Briefly, the excised tumor was fixed in formalin, embedded in paraffin and 4 μm thick slides were subsequently deparaffinized, rehydrated and washed in deionized water.…”
Section: Orthotopic Pancreatic Cancer Modelmentioning
Pancreatic cancer is one of the most lethal solid malignancies, with few treatment options. We have recently shown that expression of protease activated receptor (PAR)-1 in the tumor microenvironment drives the progression and induces the chemoresistance of pancreatic cancer. As thrombin is the prototypical PAR-1 agonist, here we address the effects of the direct thrombin inhibitor dabigatran on pancreatic cancer growth and drug resistance in an orthotropic pancreatic cancer model. We show that dabigatran treatment did not affect primary tumor growth, whereas it significantly increased tumor dissemination throughout the peritoneal cavity. Increased dissemination was accompanied by intratumoral bleeding and increased numbers of aberrant and/or collapsed blood vessels in the primary tumors. In combination with gemcitabine, dabigatran treatment limited primary tumor growth, did not induce bleeding complications and prevented tumor cell dissemination. Dabigatran was, however, not as efficient as genetic ablation of PAR-1 in our previous study, suggesting that thrombin is not the main PAR-1 agonist in the setting of pancreatic cancer. Overall, we show that dabigatran potentiates gemcitabine-induced growth inhibition of pancreatic cancer but does not affect primary tumor growth when used as monotherapy.
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