scholarly journals MEHP-induced rat testicular inflammation does not exacerbate germ cell apoptosis

Reproduction ◽  
2018 ◽  
Vol 156 (1) ◽  
pp. 35-46 ◽  
Author(s):  
Jorine J L P Voss ◽  
Angela R Stermer ◽  
Rashin Ghaffari ◽  
Richa Tiwary ◽  
John H Richburg
Keyword(s):  
Germ Cell ◽  
Immune Cells ◽  
Neutrophil Infiltration ◽  
Inflammatory Monocytes ◽  
Cell Antibody ◽  
Infiltrating Cells ◽  
Fischer Rats ◽  
Testicular Injury ◽  
Ethylhexyl Phthalate ◽  
Testicular Inflammation

The testis is an organ that maintains an immune suppressive environment. We previously revealed that exposure of pre-pubertal rats to an acute dose of a well-described Sertoli cell toxicant, mono-(2-ethylhexyl) phthalate (MEHP), leads to an accumulation of CD11b+ immune cells in the testicular interstitial space that closely correlates with a robust incidence of germ cell (GC) apoptosis. Here, we test the hypothesis that the infiltrating immune cells contribute to GC apoptosis. Postnatal day 28 Fischer rats that received an oral dose of 700 mg/kg MEHP showed a significant infiltration of both CD11bc+/CD68+/CD163− macrophages and neutrophils. The infiltration peaked at 12 h, but had reduced by 48 h. Testicular macrophages from MEHP-treated rats showed significantly upregulated expression of Tnfa and Il6, and the Arg1/Nos2 ratio was reduced compared to controls. However, small increases in anti-inflammatory genes Il10 and Tgfb1 were also observed. Depletion of circulating monocytes with clodronate liposomes prior to MEHP treatment reduced the macrophage influx into the testis, but did not lower GC apoptosis. Additionally, depletion of neutrophils using an anti-polymorphonuclear cell antibody prevented both macrophage and neutrophil infiltration into the testis, and also did not affect GC apoptosis. Together, these results show that exposure to MEHP leads to a rapid and temporary influx of pro-inflammatory monocytes and neutrophils in the interstitium of the testis. However, with this acute dosing paradigm, these infiltrating leukocytes do not appear to contribute to MEHP-induced testicular GC apoptosis leaving the functional significance of these infiltrating cells in the pathogenesis of MEHP-induced testicular injury unresolved.

scholarly journals Peritubular macrophages and spermatogonia are sequentially increased in the testis of rats after mono-(2-ethylhexyl) phthalate exposure

2019 ◽  
Author(s):  
Ross Gillette ◽  
Richa Tiwary ◽  
Jorine JLP Voss ◽  
Shavini N Hewage ◽  
John H Richburg
Keyword(s):  
Corn Oil ◽  
Male Rats ◽  
Acute Injury ◽  
Seminiferous Tubules ◽  
Mhc Ii ◽  
Cell Niche ◽  
Testicular Injury ◽  
Phthalate Metabolite ◽  
Ethylhexyl Phthalate ◽  
Testicular Inflammation

AbstractPeripubertal exposure to the phthalate metabolite mono-(2-ethylhexyl) phthalate (MEHP) in rodents causes testicular inflammation, spermatocyte apoptosis, and disruption of the blood-testis barrier. The MEHP-induced inflammation response includes an infiltration of macrophages and neutrophils to the testes, although the cause and purpose of this response is unknown. Recently, a population of testicular macrophages phenotypically distinct from those resident in the interstitium was described in mice. Testicular peritubular macrophages aggregate near the spermatogonial stem cell niche and are believed to stimulate their differentiation. We hypothesized that if testicular peritubular macrophages do indeed stimulate spermatogonial differentiation, MEHP exposure would result in an increase of peritubular macrophages to stimulate the replacement of lost spermatocytes. Male rats were exposed to 700 mg/kg MEHP or corn oil (vehicle control) via oral gavage at PND 28 and euthanized at 48 hours, 1 week, or 2 weeks later. Tubules were stained with immunofluorescent markers for macrophages and undifferentiated spermatogonia. Peritubular macrophages were observed in rat testis similar to those previously described in mice: MHC-II+ cells on the surface of seminiferous tubules with heterogeneous morphology. Quantification of MHC-II+ cells revealed that, unlike in the mouse, their numbers did not increase through puberty. MEHP increased macrophage presence by six-fold 48-hours after exposure and remained elevated by two-fold two weeks after exposure. An increase of differentiating spermatogonia occurred two weeks after MEHP exposure. Taken together, our results suggest that peritubular macrophages play a crucial role in the testis response to acute injury and the subsequent recovery of spermatogenesis.Summary SentencePhthalate-induced testicular injury results in an increase of specialized peritubular macrophages that may assist in the recovery of spermatogenesis.

Abstract P145: Renal Inflammation and Injury is Associated with Increased Lymphangiogenesis in Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sterling C Kneedler ◽  
Lauren Phillips ◽  
Kayla R Hudson ◽  
Katharine M Beckman ◽  
Alan R Parrish ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Immune System ◽  
Immune Cells ◽  
Lymphatic Vessels ◽  
Macrophage Infiltration ◽  
Shr Rats ◽  
Renal Inflammation ◽  
Immune System Activation ◽  
System Activation ◽  
Fischer Rats

Hypertension is associated with immune system activation and inflammation. Renal infiltration of both innate and adaptive immune cells contributes to injury, dysfunction, and increased blood pressure. Activated immune cells that exit blood vessels into the interstitium then travel through lymphatic vessels to draining lymph nodes where they signal to other immune cells to increase the immune response. It is unknown how renal lymphatic vessels change in the context of hypertension, immune system activation, inflammation, and injury. We hypothesized that renal macrophage infiltration, inflammation, and injury would significantly increase lymphangiogenesis in various strains of rats. SHR rats that exhibit hypertension and renal injury (SHR-A3 strain) had significantly increased numbers of renal lymphatic vessels at 40 weeks of age compared to WKY controls (total of 3 fields of view: 52 ± 1 vs. 28 ± 1; p<0.05). This was associated with increased renal macrophage infiltration. SHR rats that exhibit hypertension but minimal renal injury (SHR-B2 strain) had significantly less renal lymphatic vessel numbers compared to WKY controls (25 ± 2 vs. 28 ± 1; p<0.05) and normal levels of macrophages. The signals for lymphangiogenesis, VEGF-C and its receptor VEGF-R3, were both increased significantly at the protein level in the kidneys of SHR-A3 rats at 18 weeks but not different in the kidneys of SHR-B2 rats compared to WKY controls. To test whether the increased lymphangiogensis is due to hypertension and/or renal inflammation and injury, we obtained kidneys from Fischer 344 rats that exhibit normal blood pressure but develop renal inflammation and injury as they age. Compared to kidneys from control 4-month old Fischer rats, kidneys from 20-month and 24-month old Fischer rats had significantly increased numbers of lymphatic vessels (32 ± 3 vs. 74 ± 1 vs. 110 ± 6, respectively; p<0.05) and this was also associated with increased macrophage infiltration. Protein levels of VEGF-C and VEGF-R3 were increased significantly in 20-month old Fischer rats compared to 4-month old controls. These data together demonstrate that renal immune cell infiltration, inflammation, and injury increases lymphangiogenesis.

scholarly journals A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Maria Isabel Carvalho ◽  
Ricardo Silva-Carvalho ◽  
Isabel Pires ◽  
Justina Prada ◽  
Rodolfo Bianchini ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Cells ◽  
Mammary Cancer ◽  
Inflammatory Cells ◽  
Mammary Carcinogenesis ◽  
Signaling Molecules ◽  
Comparative Approach ◽  
Human Breast ◽  
Infiltrating Cells ◽  
Inflammatory State

Infiltrating cells of the immune system are widely accepted to be generic constituents of tumor microenvironment. It has been well established that the development of mammary cancer, both in humans and in dogs, is associated with alterations in numbers and functions of immune cells at the sites of tumor progression. These tumor infiltrating immune cells seem to exhibit exclusive phenotypic and functional characteristics and mammary cancer cells can take advantage of signaling molecules released by them. Cancer related inflammation has an important role in mammary carcinogenesis, contributing to the acquisition of core hallmark capabilities that allow cancer cells to survive, proliferate, and disseminate. Indeed, recent studies in human breast cancer and in canine mammary tumors have identified a growing list of signaling molecules released by inflammatory cells that serve as effectors of their tumor-promoting actions. These include the COX-2, the tumor EGF, the angiogenic VEGF, other proangiogenic factors, and a large variety of chemokines and cytokines that amplify the inflammatory state. This review describes the intertwined signaling pathways shared by T-lymphocytic/macrophage infiltrates and important tissue biomarkers in both human and dog mammary carcinogenesis.

scholarly journals FLIP: a novel regulator of macrophage differentiation and granulocyte homeostasis

Blood ◽  
2010 ◽  
Vol 116 (23) ◽  
pp. 4968-4977 ◽  
Author(s):  
Qi-Quan Huang ◽  
Harris Perlman ◽  
Zan Huang ◽  
Robert Birkett ◽  
Lixin Kan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Ex Vivo ◽  
Death Receptor ◽  
Premature Death ◽  
Neutrophil Infiltration ◽  
Extramedullary Hematopoiesis ◽  
Macrophage Differentiation ◽  
Inflammatory Monocytes ◽  
Inflammatory Phenotype

Abstract FLIP is a well-established suppressor of death receptor-mediated apoptosis. To define its essential in vivo role in myeloid cells, we generated and characterized mice with Flip conditionally deleted in the myeloid lineage. Myeloid specific Flip-deficient mice exhibited growth retardation, premature death, and splenomegaly with altered architecture and extramedullary hematopoiesis. They also displayed a dramatic increase of circulating neutrophils and multiorgan neutrophil infiltration. In contrast, although circulating inflammatory monocytes were also significantly increased, macrophages in the spleen, lymph nodes, and the peritoneal cavity were reduced. In ex vivo cultures, bone marrow progenitor cells failed to differentiate into macrophages when Flip was deleted. Mixed bone marrow chimera experiments using cells from Flip-deficient and wild-type mice did not demonstrate an inflammatory phenotype. These observations demonstrate that FLIP is necessary for macrophage differentiation and the homeostatic regulation of granulopoiesis.

scholarly journals Impact of S1P Mimetics on Mesenteric Ischemia/Reperfusion Injury

2020 ◽  
Vol 13 (10) ◽  
pp. 298
Author(s):  
Francesco Potì ◽  
Carmine Giorgio ◽  
Irene Zini ◽  
Jerzy-Roch Nofer ◽  
Valentina Vivo ◽  
...  
Keyword(s):  
Immune Cells ◽  
Mesenteric Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Protective Action ◽  
Neutrophil Infiltration ◽  
Lipid Mediator ◽  
Receptor Subtypes ◽  
Barrier Integrity ◽  
Epithelial Barriers

Mesenteric ischemia/reperfusion (I/R), following the transient deprivation of blood flow to the gut, triggers an acute flogistic process involving the disruption of endothelial and epithelial barriers integrity, the activation of immune cells, and the abundant release of inflammatory mediators. Among them, the lipid mediator sphingosine-1-phosphate (S1P) is involved in maintaining epithelial and endothelial barrier integrity and in governing the migration of immune cells through the interaction with S1P1–5 receptors. Therefore, the present work aims to investigate the involvement of S1P signaling in intestinal I/R-induced injury by studying the effects of FTY720, the non-selective S1P1,3–5 agonist, and comparing them with the responses to ozanimod, selective S1P1,5 agonist, in a murine model of gut I/R. Intestinal edema, gut and lung neutrophil infiltration, and oxidative stress were evaluated through biochemical and morphological assays. The collected results highlight the protective action of FTY720 against the inflammatory cascade elicited by mesenteric I/R injury, mainly through the control of vascular barrier integrity. While these beneficial effects were mimicked by ozanimod and can be therefore attributed largely to the effects exerted by FTY720 on S1P1, the recruitment of myeloid cells to the injured areas, limited by FTY720 but not by ozanimod, rather suggests the involvement of other receptor subtypes.

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