Hector Pons - Academia.edu (original) (raw)
Papers by Hector Pons
Journal of Immunological Methods, 1992
A modified colorimetric method for the measurement of phagocytosis and antibody-dependent cell cy... more A modified colorimetric method for the measurement of phagocytosis and antibody-dependent cell cytotoxicity
Investigacion Clinica, 2013
Las distrofias musculares de Duchenne y Becker (DMD/BMD) son enfermedades neuromusculares recesiv... more Las distrofias musculares de Duchenne y Becker (DMD/BMD) son enfermedades neuromusculares recesivas ligadas a X producidas por mutaciones alelicas en el gen de la distrofina humana. Este estudio presenta los primeros resultados venezolanos en los que se realiza diagnostico molecular de DMD/DMB mediante amplificacion multiple de los 14 exones mas propensos a delecion dentro del gen. En 24 pacientes venezolanos, no relacionados, se encontro un 37.5 % de deleciones intragenicas y el 77,7% de ellas estuvo localizado en la region ";caliente"; comprendida desde el exon 44 al 55. Nuestra frecuencia de delecion es menor a la reportada en estudios en poblaciones europeas y norteamericanas y semejante a la de algunas poblaciones asiaticas. La baja frecuencia detectada en nuestros pacientes podria estar relacionada a la existencia de diferentes mutaciones en otras regiones del gen de la distrofma que determinan una heterogeneidad molecular en la etiologia de la DMD/DMB en Venezuela.
Biomolecules
Heat shock protein 70 (HSP70) production is a stress-generated cellular response with high inters... more Heat shock protein 70 (HSP70) production is a stress-generated cellular response with high interspecies homology. HSP70 has both chaperone and cytokine functions and may induce, depending on the context, tolerogenic anti-inflammatory reactivity or immunogenic and autoimmune reactivity. Intracellular (chaperoning transit of antigens to MHC in antigen-presenting cells) and extracellular HSP70-related effects are associated with hypertension, which is an inflammatory condition recognized as the most important risk factor for cardiovascular disease mortality. Here, we review (a) the relationship between HSP70, inflammation and immune reactivity, (b) clinical evidence relating to stress, HSP70 and anti-HSP70 reactivity with primary hypertension and (c) experimental data showing that salt-sensitive hypertension is associated with delayed hypersensitivity to HSP70. This is a consequence of anti-HSP70 reactivity in the kidneys and may be prevented and corrected by the T-cell-driven inhibiti...
Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt-sensitive hyp... more Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt-sensitive hypertension
Journal of the American Society of Nephrology, 2001
Rats that are administered angiotensin II (AngII) for 2 wk develop persistent salt-sensitive hype... more Rats that are administered angiotensin II (AngII) for 2 wk develop persistent salt-sensitive hypertension, which can be prevented by the immunosuppressor mycophenolate mofetil (MMF) given during the AngII infusion. This study examined the contribution of glomerular hemodynamics (GFR dynamics) in the post-AngII hypertensive response to a high-salt diet (HSD) and the effect of MMF treatment. During AngII administration, rats developed severe hypertension (systolic BP [SBP], 185 Ϯ 3.9 mmHg), proteinuria, afferent and efferent vasoconstriction, and glomerular hypertension. Rats that received AngIIϩMMF showed similar responses to AngII; however, they developed lower proteinuria (P Ͻ 0.05). At 2 wk, AngII was withdrawn and SBP returned toward normal. Rats were then placed on an HSD (4% NaCl), resulting in a progressive increase in SBP (155 Ϯ 8.2 mmHg at week 1 and 163 Ϯ 4.5 mmHg at week 5). GFR dynamic alterations persisted after AngII was stopped, i.e., afferent and efferent vasoconstriction, decreased glomerular plasma flow and singlenephron GFR, and lower ultrafiltration coefficient. These changes correlated with the thickening of the afferent arteriole and with focal tubulointerstitial injury. In the AngIIϩMMF group, SBP remained unchanged throughout the HSD period (146 Ϯ 2.3 mmHg at week 1 and 148 Ϯ 4.4 mmHg at week 5) in association with less afferent arteriolar thickening and tubulointerstitial injury. Single-nephron GFR, glomerular plasma flow, efferent resistance, and ultrafiltration coefficient returned to normal with a significant reduction in afferent resistance. These results suggest a critical role of cortical vasoconstriction in salt-sensitive hypertension. The MMF-induced prevention of these changes suggests that immune mechanisms are involved in the vasoconstrictive response.
AJP: Renal Physiology, 2012
Hypertension affects one-third of the adult population of the world. The causes of hypertension a... more Hypertension affects one-third of the adult population of the world. The causes of hypertension are incompletely understood, but relative impairment of sodium excretion is central to its pathogenesis. Immune cell infiltration in the kidney is a constant finding in hypertension that in association with local angiotensin and oxidants causes a defect in sodium excretion. However, it is unclear if the T cell influx into the kidney responds to nonspecific chemokine cues or is due to antigen-driven immune attraction. We found that T cells in experimentally induced salt-driven hypertension present a CD4 clonal response to heat shock protein 70 (HSP70) that is overexpressed in the kidney. We used a highly preserved amino acid sequence within the HSP molecule to induce immune tolerance associated with the generation of IL-10 producing regulatory T cells. Immune tolerant rats to HSP70 developed minimal renal inflammation and were protected from the development of salt-sensitive hypertension. ...
American Journal of Nephrology, 2010
Nitric oxide (NO) availability plays a critical role in the regulation of blood pressure, endothe... more Nitric oxide (NO) availability plays a critical role in the regulation of blood pressure, endothelial function and arterial structure. Many of the biological actions of NO are mediated by 3'5'-guanosine monophosphate (cGMP), which is rapidly degraded by cGMP phosphodiesterase (PDE). Short-term cardiovascular effects of PDE inhibitors have been studied but the changes resulting from their chronic administration in hypertension have not been evaluated. We investigated if retarding the degradation of cGMP by long-term inhibition of PDE-5 would have beneficial consequences in spontaneously hypertensive rats (SHR), a commonly used experimental model of human essential hypertension. Subgroups of hypertensive 13-week-old male SHR and normotensive Wistar-Kyoto rats were treated with sildenafil, 2.5 mg/kg/day, or vehicle, by gastric gavage for 6 months. As expected, the untreated SHR had endothelial dysfunction and a steady increment of the blood pressure. In contrast, chronic sildenafil administration reversed endothelial dysfunction, reduced renal oxidative stress and renal macrophage accumulation, and ameliorated the severity of hypertension in SHR. These results demonstrate beneficial effects of long-term PDE-5 inhibition in SHR and suggest that its use as an adjunct therapy in essential hypertension should be investigated.
Acta Histochemica, 1992
ABSTRACT The distribution of perikarya showing substance P- (SP) or calcitonin gene-related pepti... more ABSTRACT The distribution of perikarya showing substance P- (SP) or calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) in the rat trigeminal ganglion (TG) were investigated by means of immunohistochemical methods. Approximately 50% of the perikarya contain CGRP while SP-LI was observed in 1/3 of the cells. IR fibres were seen to leave the ganglion via the ophthalmic, maxillary, and mandibular nerves. The combination of peptide histochemistry and retrograde labelling of cells in the ganglion following injection of a fluorescent tracer into the pineal gland reveals that few SP- or CGRP-LI trigeminal neurons innervate the pineal gland. In contrast, the vast majority of perikarya in the TG were labelled upon application of the tracer to the meningeal surface supporting the view that meninges and meningeal arteries in rodents are heavily innervated by SP- and CGRP-LI trigeminal neurons.
Atherosclerosis, 2000
Immunosuppressive therapy has been shown to either improve or, more frequently, enhance the devel... more Immunosuppressive therapy has been shown to either improve or, more frequently, enhance the development of atherosclerosis. We tested the effect of mycophenolate mofetil (MMF), an inhibitor of nucleotide synthesis widely used in transplant therapy, in diet-induced atherosclerosis in the rabbit. Two groups (n= 10 each) of New Zealand White (NZW) rabbits were fed a 1% cholesterol diet for 12 weeks. One group received MMF (CHOL +MMF group) by gastric gavage (30 mg/kg daily) and the other group (CHOL) received the same volume of saline by the same route. There were no differences in the serum cholesterol (mean values ]30 mmol/l in both groups after 2 weeks) or in the triglyceride, blood sugar, total protein, and albumin serum levels and weight gain in both groups of animals. The cholesterol-fed untreated rabbits had atherosclerotic plaques covering 43.9.1 9SD 16.40% of their thoracic aorta and 41.9 922.59% of their abdominal aorta, while the MMF treated group had 18.5 97.17% and 17.7 9 9.71%, respectively (PB 0.01). The cholesterol content of the aorta (mg/g) in the cholesterol-fed untreated group was 4.61 9 SD 1.21 in the thoracic aorta and 4.54 92.07 in the abdominal aorta, whereas the MMF treated group had and 2.83 9 0.84 and 2.77 91.44, respectively (P B0.01). Infiltrating macrophages (RAM 11 positive cells/100 nuclei) in the intimal layer of the aorta were 58.4 9SD26.16 in the CHOL group and 8.595.51 in the CHOL+MMF group: (P B0.001). CD18 positive cells/100 nuclei were 27.4 917.6 in the CHOL group and 5.3 93.82 in the CHOL + MMF group (P B0.01), and the intima/media ratio was 0.6690.11 in the CHOL group and 0.309 0.09 in the MMF treated rabbits (PB 0.001). MMF also reduced proliferating smooth muscle cells (HHF35 positive) infiltrating between the macrophages. These results indicate that MMF ameliorates importantly the atherogenic potential of a high cholesterol diet and this effect is associated with a reduction in macrophage and foam cell infiltration and smooth muscle cell proliferation and infiltration. Since chronic treatment with this drug is given routinely in various clinical conditions with relatively minor side effects, consideration may be given to its use as adjuvant therapy in artheriosclerotic cardiovascular disease.
Kidney International, 2003
Annals of Allergy, Asthma & Immunology, 2012
Respiratory syncytial virus (RSV) infection is associated to episodic exacerbations of asthma inv... more Respiratory syncytial virus (RSV) infection is associated to episodic exacerbations of asthma involving alveolar macrophages and chemokine production. The aim of this study was to determine the circulating levels of monocyte chemotactic protein 1 (MCP-1), regulated on activation normal T cell expressed and secreted (RANTES), and substance P (SP) in patients with and without asthma with acute respiratory RSV infection and the chemokine profile in RSV- infected monocyte cultures from normal individuals and individuals with asthma. In this regard, 31 adult patients with acute respiratory infection (15 patients with asthma) were studied. MCP-1, RANTES and SP were measured in serum and in supernatants from monocyte cultures by enzyme-linked immunosorbent assay (ELISA). Increased levels of MCP-1 and RANTES were observed in serum from patients with asthma related to RSV infection. RSV-infected monocyte cultures from healthy individuals showed increased content of those chemokines, and monocyte cultures from patients with asthma showed increased expression of MCP-1. These data show that RSV infection induces increased circulating level of chemokines in patients with asthma, and this finding could be mediated in part by the interaction virus-monocyte.
Physiological reviews, Jul 1, 2017
High blood pressure is present in more than one billion adults worldwide and is the most importan... more High blood pressure is present in more than one billion adults worldwide and is the most important modifiable risk factor of death resulting from cardiovascular disease. While many factors contribute to the pathogenesis of hypertension, a role of the immune system has been firmly established by a large number of investigations from many laboratories around the world. Immunosuppressive drugs and inhibition of individual cytokines prevent or ameliorate experimental hypertension, and studies in genetically-modified mouse strains have demonstrated that lymphocytes are necessary participants in the development of hypertension and in hypertensive organ injury. Furthermore, immune reactivity may be the driving force of hypertension in autoimmune diseases. Infiltration of immune cells, oxidative stress, and stimulation of the intrarenal angiotensin system are induced by activation of the innate and adaptive immunity. High blood pressure results from the combined effects of inflammation-indu...
Journal of Hypertension Supplement Official Journal of the International Society of Hypertension, Jun 1, 2002
This work summarizes recent evidence that suggests that renal infiltration with immune cells play... more This work summarizes recent evidence that suggests that renal infiltration with immune cells plays a role in the pathogenesis of salt-sensitive hypertension. The presence of immunocompetent cells is a conspicuous finding in conditions associated with hypertension induced or maintained by a high salt intake. Studies in models of salt-sensitive hypertension following angiotensin II infusion and nitric oxide synthesis inhibition indicate that a reduction in the tubulointerstitial infiltration of lymphocytes and macrophages during the induction period results in protection from the subsequent development of salt-sensitive hypertension. Reduction of the renal immune infiltrate in spontaneously hypertensive rats results in near normalization of the blood pressure. The reduction in the immune infiltrate is associated with a reduction in the number of cells expressing angiotensin II (some of which are immune cells) and a reduction in renal oxidative stress. Since increased intrarenal angiotensin activity tends to reduce filtered sodium and increase sodium reabsorption, and the tubulointerstitial damage resulting from oxidative stress can induce a shift to the right in the pressure-natriuresis relationship, these findings suggest potential mechanisms by which the immune infiltrate could induce or worsen salt-driven hypertension.
Investigacion Clinica, Mar 1, 2005
Journal of Obstetrics and Gynaecology Research, 2015
The objective of this study was to determine the ability of biochemical analytes to identify adve... more The objective of this study was to determine the ability of biochemical analytes to identify adverse outcomes in pregnancies with Turner syndrome. Maternal serum and amniotic fluid (AF) marker concentrations were measured in 73 singleton pregnancies with Turner syndrome (10-22 weeks of gestation). Fetal Turner syndrome was definitively established by cytogenetic analysis. Two subgroups, fetuses with hydrops fetalis versus fetuses with cystic hygroma, were compared. Receiver operating characteristic curves and relative risk were established for a cut-off multiples of the median ≥3.5 for β-subunit of human chorionic gonadotropin (hCG) or AF alpha-fetoprotein (AFP). Forty-nine (67%) of 73 pregnant women had an abnormal maternal serum. While levels of pregnancy-associated plasma protein-A and free β-subunit (fβ)-hCG were not different to those of the control group, AFP, unconjugated estriol and β-hCG concentrations were significantly different in the study group (P < 0.05), when compared to those of unaffected pregnancies. Levels of β-hCG in pregnancies with hydrops fetalis were significantly higher than in those with cystic hygroma (P <0.0001), as were AF-AFP concentrations (P <0.0015). In addition, abnormalities in both maternal serum β-hCG and AF-AFP predicted fetal death. The relative risk of adverse obstetric outcome was 10.667 (P = 0.0004; 95% confidence interval [CI]: 1.554-73.203) for β-hCG and 2.19 (P = 0.0256; 95% CI: 1.001 to 4.779), for AF-AFP. Maternal serum β-hCG and AF-AFP levels may preferentially identify those Turner syndrome pregnancies with the highest risk of fetal death.
Investigación clínica
The purpose of this work was to determine the expression of type Th1 cytokines: IL-2 and IFNgamma... more The purpose of this work was to determine the expression of type Th1 cytokines: IL-2 and IFNgamma, and Th2: IL-4 and IL-6, as well as TNF-alpha in patients with precancerous lesions of the uterine cervix and their relationship with the human papiloma virus (HPV). 30 patients with precancerous lesions (NIC 1: 70%, NIC 2: 16.7% and NIC 3: 1.3%) and 9 normal controls were studied. A clinical history, gynecological evaluation, cytology and an uterine biopsy were carried out in each patient and control. PCR was used for the diagnosis of HPV. IFN-gamma expression (positive cells/field) was increased in patients with NIC (5.06 +/- 4.7 vs 0 in the control group; p < 0.05). TNFa was a little higher in pathologycal tissues than in the controls (5.23 +/- 3.63 vs 1.55 +/- 2.65; p < 0.05). IL-2 was higher in pathologycal cases than in the controls (8.73 +/- 5.23 vs 0.33 +/- 1, p < 0.05). IL-4 were expressed in both, patients and controls (6.53 +/- 5.23 vs 5.77 +/- 7.32). IL-6 was also higher in patients (4.63 +/- 3.34 vs 0.77 +/- 2.33; p < 0.05). When the HPV status was considered, only IFN-gamma (p < 0.05) and IL-2 (p < 0.05) were significantly higher in HPV positive patients (n = 4) compared to controls. When HPV+ patients were compared with HPV- patients, only IFNgamma was significant (11.5 +/- 5 vs 4.07 +/- 3.8; p < 0.05). In conclusion, Type Th1 immune response prevails in patients with precancerous lesions, whether they are HPV positive or not.
![Research paper thumbnail of [Effects of mycophenolate mofetil in ischemic acute renal failure in rats]](https://attachments.academia-assets.com/78685612/thumbnails/1.jpg)
](Nefrología : publicación oficial de la Sociedad Española Nefrologia, 2007
Mycophenolate mofetil (MMF) is a purine synthesis inhibitor commonly used as immunosupresive agen... more Mycophenolate mofetil (MMF) is a purine synthesis inhibitor commonly used as immunosupresive agent in transplantation. Kidney grafts undergo more or less prolonged cold ischemia after harvesting which results in variable degrees of ischemia reperfusion injury. To determine whether the inhibition of early events of cellular infiltration may influence the severity of damage induced by ischemic acute renal failure, 45 Sprague Dawley rats were given MMF at a dose of 20mg/kg/day (MMF-rats) by gavage 2 days before (pre-MMF group, n=15) or after (post-MMF group, n=15) clamping the left renal artery for 40 minutes followed by rigt-sided nephrectomy. (control group, n=15) received vehicle. Serum Creatinine (Screat) was measured daily in all groups. On the 2nd post-ischemic day Screat was significantly lower (p=0.001) in pre-MMF group compared with post-MMF group and control group (4 +/- 2mg/dl post-MMF group vs 1.7 +/- 1.2 mg/dl pre-MMF group, control group 5+/-2, p< 0.05). Kidney biopsie...
Neurochemical research, 2003
The effect of melatonin (MLT) on the brain levels of tumor necrosis factor alpha (TNF-alpha) and ... more The effect of melatonin (MLT) on the brain levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in Venezuelan equine encephalomyelitis (VEE) virus infection was determined. Brain homogenates from mice inoculated with 10 LD50 of VEE virus, untreated or treated with 500 microg MLT/kg body weight were assayed by ELISA to measure the levels of TNF-alpha and IL-1beta. MLT was injected daily starting 3 days before and continuing to 7 days after virus inoculation. Infected mice treated with MLT showed decreased levels of TNF-alpha when compared to the untreated infected mice on days 1, 3, 4, and 5 postinoculation (P < 0.001). In contrast, IL-1beta levels increased from days 1 to 5 in the infected mice treated with MLT when compared with the untreated infected animals (P < 0.01). The results suggest that the protective effect of MLT on the VEE virus infection could be due, among other factors, to a decrease in TNF-alpha synthesis along with an increase in...
Journal of Immunological Methods, 1992
A modified colorimetric method for the measurement of phagocytosis and antibody-dependent cell cy... more A modified colorimetric method for the measurement of phagocytosis and antibody-dependent cell cytotoxicity
Investigacion Clinica, 2013
Las distrofias musculares de Duchenne y Becker (DMD/BMD) son enfermedades neuromusculares recesiv... more Las distrofias musculares de Duchenne y Becker (DMD/BMD) son enfermedades neuromusculares recesivas ligadas a X producidas por mutaciones alelicas en el gen de la distrofina humana. Este estudio presenta los primeros resultados venezolanos en los que se realiza diagnostico molecular de DMD/DMB mediante amplificacion multiple de los 14 exones mas propensos a delecion dentro del gen. En 24 pacientes venezolanos, no relacionados, se encontro un 37.5 % de deleciones intragenicas y el 77,7% de ellas estuvo localizado en la region ";caliente"; comprendida desde el exon 44 al 55. Nuestra frecuencia de delecion es menor a la reportada en estudios en poblaciones europeas y norteamericanas y semejante a la de algunas poblaciones asiaticas. La baja frecuencia detectada en nuestros pacientes podria estar relacionada a la existencia de diferentes mutaciones en otras regiones del gen de la distrofma que determinan una heterogeneidad molecular en la etiologia de la DMD/DMB en Venezuela.
Biomolecules
Heat shock protein 70 (HSP70) production is a stress-generated cellular response with high inters... more Heat shock protein 70 (HSP70) production is a stress-generated cellular response with high interspecies homology. HSP70 has both chaperone and cytokine functions and may induce, depending on the context, tolerogenic anti-inflammatory reactivity or immunogenic and autoimmune reactivity. Intracellular (chaperoning transit of antigens to MHC in antigen-presenting cells) and extracellular HSP70-related effects are associated with hypertension, which is an inflammatory condition recognized as the most important risk factor for cardiovascular disease mortality. Here, we review (a) the relationship between HSP70, inflammation and immune reactivity, (b) clinical evidence relating to stress, HSP70 and anti-HSP70 reactivity with primary hypertension and (c) experimental data showing that salt-sensitive hypertension is associated with delayed hypersensitivity to HSP70. This is a consequence of anti-HSP70 reactivity in the kidneys and may be prevented and corrected by the T-cell-driven inhibiti...
Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt-sensitive hyp... more Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt-sensitive hypertension
Journal of the American Society of Nephrology, 2001
Rats that are administered angiotensin II (AngII) for 2 wk develop persistent salt-sensitive hype... more Rats that are administered angiotensin II (AngII) for 2 wk develop persistent salt-sensitive hypertension, which can be prevented by the immunosuppressor mycophenolate mofetil (MMF) given during the AngII infusion. This study examined the contribution of glomerular hemodynamics (GFR dynamics) in the post-AngII hypertensive response to a high-salt diet (HSD) and the effect of MMF treatment. During AngII administration, rats developed severe hypertension (systolic BP [SBP], 185 Ϯ 3.9 mmHg), proteinuria, afferent and efferent vasoconstriction, and glomerular hypertension. Rats that received AngIIϩMMF showed similar responses to AngII; however, they developed lower proteinuria (P Ͻ 0.05). At 2 wk, AngII was withdrawn and SBP returned toward normal. Rats were then placed on an HSD (4% NaCl), resulting in a progressive increase in SBP (155 Ϯ 8.2 mmHg at week 1 and 163 Ϯ 4.5 mmHg at week 5). GFR dynamic alterations persisted after AngII was stopped, i.e., afferent and efferent vasoconstriction, decreased glomerular plasma flow and singlenephron GFR, and lower ultrafiltration coefficient. These changes correlated with the thickening of the afferent arteriole and with focal tubulointerstitial injury. In the AngIIϩMMF group, SBP remained unchanged throughout the HSD period (146 Ϯ 2.3 mmHg at week 1 and 148 Ϯ 4.4 mmHg at week 5) in association with less afferent arteriolar thickening and tubulointerstitial injury. Single-nephron GFR, glomerular plasma flow, efferent resistance, and ultrafiltration coefficient returned to normal with a significant reduction in afferent resistance. These results suggest a critical role of cortical vasoconstriction in salt-sensitive hypertension. The MMF-induced prevention of these changes suggests that immune mechanisms are involved in the vasoconstrictive response.
AJP: Renal Physiology, 2012
Hypertension affects one-third of the adult population of the world. The causes of hypertension a... more Hypertension affects one-third of the adult population of the world. The causes of hypertension are incompletely understood, but relative impairment of sodium excretion is central to its pathogenesis. Immune cell infiltration in the kidney is a constant finding in hypertension that in association with local angiotensin and oxidants causes a defect in sodium excretion. However, it is unclear if the T cell influx into the kidney responds to nonspecific chemokine cues or is due to antigen-driven immune attraction. We found that T cells in experimentally induced salt-driven hypertension present a CD4 clonal response to heat shock protein 70 (HSP70) that is overexpressed in the kidney. We used a highly preserved amino acid sequence within the HSP molecule to induce immune tolerance associated with the generation of IL-10 producing regulatory T cells. Immune tolerant rats to HSP70 developed minimal renal inflammation and were protected from the development of salt-sensitive hypertension. ...
American Journal of Nephrology, 2010
Nitric oxide (NO) availability plays a critical role in the regulation of blood pressure, endothe... more Nitric oxide (NO) availability plays a critical role in the regulation of blood pressure, endothelial function and arterial structure. Many of the biological actions of NO are mediated by 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-guanosine monophosphate (cGMP), which is rapidly degraded by cGMP phosphodiesterase (PDE). Short-term cardiovascular effects of PDE inhibitors have been studied but the changes resulting from their chronic administration in hypertension have not been evaluated. We investigated if retarding the degradation of cGMP by long-term inhibition of PDE-5 would have beneficial consequences in spontaneously hypertensive rats (SHR), a commonly used experimental model of human essential hypertension. Subgroups of hypertensive 13-week-old male SHR and normotensive Wistar-Kyoto rats were treated with sildenafil, 2.5 mg/kg/day, or vehicle, by gastric gavage for 6 months. As expected, the untreated SHR had endothelial dysfunction and a steady increment of the blood pressure. In contrast, chronic sildenafil administration reversed endothelial dysfunction, reduced renal oxidative stress and renal macrophage accumulation, and ameliorated the severity of hypertension in SHR. These results demonstrate beneficial effects of long-term PDE-5 inhibition in SHR and suggest that its use as an adjunct therapy in essential hypertension should be investigated.
Acta Histochemica, 1992
ABSTRACT The distribution of perikarya showing substance P- (SP) or calcitonin gene-related pepti... more ABSTRACT The distribution of perikarya showing substance P- (SP) or calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) in the rat trigeminal ganglion (TG) were investigated by means of immunohistochemical methods. Approximately 50% of the perikarya contain CGRP while SP-LI was observed in 1/3 of the cells. IR fibres were seen to leave the ganglion via the ophthalmic, maxillary, and mandibular nerves. The combination of peptide histochemistry and retrograde labelling of cells in the ganglion following injection of a fluorescent tracer into the pineal gland reveals that few SP- or CGRP-LI trigeminal neurons innervate the pineal gland. In contrast, the vast majority of perikarya in the TG were labelled upon application of the tracer to the meningeal surface supporting the view that meninges and meningeal arteries in rodents are heavily innervated by SP- and CGRP-LI trigeminal neurons.
Atherosclerosis, 2000
Immunosuppressive therapy has been shown to either improve or, more frequently, enhance the devel... more Immunosuppressive therapy has been shown to either improve or, more frequently, enhance the development of atherosclerosis. We tested the effect of mycophenolate mofetil (MMF), an inhibitor of nucleotide synthesis widely used in transplant therapy, in diet-induced atherosclerosis in the rabbit. Two groups (n= 10 each) of New Zealand White (NZW) rabbits were fed a 1% cholesterol diet for 12 weeks. One group received MMF (CHOL +MMF group) by gastric gavage (30 mg/kg daily) and the other group (CHOL) received the same volume of saline by the same route. There were no differences in the serum cholesterol (mean values ]30 mmol/l in both groups after 2 weeks) or in the triglyceride, blood sugar, total protein, and albumin serum levels and weight gain in both groups of animals. The cholesterol-fed untreated rabbits had atherosclerotic plaques covering 43.9.1 9SD 16.40% of their thoracic aorta and 41.9 922.59% of their abdominal aorta, while the MMF treated group had 18.5 97.17% and 17.7 9 9.71%, respectively (PB 0.01). The cholesterol content of the aorta (mg/g) in the cholesterol-fed untreated group was 4.61 9 SD 1.21 in the thoracic aorta and 4.54 92.07 in the abdominal aorta, whereas the MMF treated group had and 2.83 9 0.84 and 2.77 91.44, respectively (P B0.01). Infiltrating macrophages (RAM 11 positive cells/100 nuclei) in the intimal layer of the aorta were 58.4 9SD26.16 in the CHOL group and 8.595.51 in the CHOL+MMF group: (P B0.001). CD18 positive cells/100 nuclei were 27.4 917.6 in the CHOL group and 5.3 93.82 in the CHOL + MMF group (P B0.01), and the intima/media ratio was 0.6690.11 in the CHOL group and 0.309 0.09 in the MMF treated rabbits (PB 0.001). MMF also reduced proliferating smooth muscle cells (HHF35 positive) infiltrating between the macrophages. These results indicate that MMF ameliorates importantly the atherogenic potential of a high cholesterol diet and this effect is associated with a reduction in macrophage and foam cell infiltration and smooth muscle cell proliferation and infiltration. Since chronic treatment with this drug is given routinely in various clinical conditions with relatively minor side effects, consideration may be given to its use as adjuvant therapy in artheriosclerotic cardiovascular disease.
Kidney International, 2003
Annals of Allergy, Asthma & Immunology, 2012
Respiratory syncytial virus (RSV) infection is associated to episodic exacerbations of asthma inv... more Respiratory syncytial virus (RSV) infection is associated to episodic exacerbations of asthma involving alveolar macrophages and chemokine production. The aim of this study was to determine the circulating levels of monocyte chemotactic protein 1 (MCP-1), regulated on activation normal T cell expressed and secreted (RANTES), and substance P (SP) in patients with and without asthma with acute respiratory RSV infection and the chemokine profile in RSV- infected monocyte cultures from normal individuals and individuals with asthma. In this regard, 31 adult patients with acute respiratory infection (15 patients with asthma) were studied. MCP-1, RANTES and SP were measured in serum and in supernatants from monocyte cultures by enzyme-linked immunosorbent assay (ELISA). Increased levels of MCP-1 and RANTES were observed in serum from patients with asthma related to RSV infection. RSV-infected monocyte cultures from healthy individuals showed increased content of those chemokines, and monocyte cultures from patients with asthma showed increased expression of MCP-1. These data show that RSV infection induces increased circulating level of chemokines in patients with asthma, and this finding could be mediated in part by the interaction virus-monocyte.
Physiological reviews, Jul 1, 2017
High blood pressure is present in more than one billion adults worldwide and is the most importan... more High blood pressure is present in more than one billion adults worldwide and is the most important modifiable risk factor of death resulting from cardiovascular disease. While many factors contribute to the pathogenesis of hypertension, a role of the immune system has been firmly established by a large number of investigations from many laboratories around the world. Immunosuppressive drugs and inhibition of individual cytokines prevent or ameliorate experimental hypertension, and studies in genetically-modified mouse strains have demonstrated that lymphocytes are necessary participants in the development of hypertension and in hypertensive organ injury. Furthermore, immune reactivity may be the driving force of hypertension in autoimmune diseases. Infiltration of immune cells, oxidative stress, and stimulation of the intrarenal angiotensin system are induced by activation of the innate and adaptive immunity. High blood pressure results from the combined effects of inflammation-indu...
Journal of Hypertension Supplement Official Journal of the International Society of Hypertension, Jun 1, 2002
This work summarizes recent evidence that suggests that renal infiltration with immune cells play... more This work summarizes recent evidence that suggests that renal infiltration with immune cells plays a role in the pathogenesis of salt-sensitive hypertension. The presence of immunocompetent cells is a conspicuous finding in conditions associated with hypertension induced or maintained by a high salt intake. Studies in models of salt-sensitive hypertension following angiotensin II infusion and nitric oxide synthesis inhibition indicate that a reduction in the tubulointerstitial infiltration of lymphocytes and macrophages during the induction period results in protection from the subsequent development of salt-sensitive hypertension. Reduction of the renal immune infiltrate in spontaneously hypertensive rats results in near normalization of the blood pressure. The reduction in the immune infiltrate is associated with a reduction in the number of cells expressing angiotensin II (some of which are immune cells) and a reduction in renal oxidative stress. Since increased intrarenal angiotensin activity tends to reduce filtered sodium and increase sodium reabsorption, and the tubulointerstitial damage resulting from oxidative stress can induce a shift to the right in the pressure-natriuresis relationship, these findings suggest potential mechanisms by which the immune infiltrate could induce or worsen salt-driven hypertension.
Investigacion Clinica, Mar 1, 2005
Journal of Obstetrics and Gynaecology Research, 2015
The objective of this study was to determine the ability of biochemical analytes to identify adve... more The objective of this study was to determine the ability of biochemical analytes to identify adverse outcomes in pregnancies with Turner syndrome. Maternal serum and amniotic fluid (AF) marker concentrations were measured in 73 singleton pregnancies with Turner syndrome (10-22 weeks of gestation). Fetal Turner syndrome was definitively established by cytogenetic analysis. Two subgroups, fetuses with hydrops fetalis versus fetuses with cystic hygroma, were compared. Receiver operating characteristic curves and relative risk were established for a cut-off multiples of the median ≥3.5 for β-subunit of human chorionic gonadotropin (hCG) or AF alpha-fetoprotein (AFP). Forty-nine (67%) of 73 pregnant women had an abnormal maternal serum. While levels of pregnancy-associated plasma protein-A and free β-subunit (fβ)-hCG were not different to those of the control group, AFP, unconjugated estriol and β-hCG concentrations were significantly different in the study group (P &amp;amp;amp;amp;amp;lt; 0.05), when compared to those of unaffected pregnancies. Levels of β-hCG in pregnancies with hydrops fetalis were significantly higher than in those with cystic hygroma (P &amp;amp;amp;amp;amp;lt;0.0001), as were AF-AFP concentrations (P &amp;amp;amp;amp;amp;lt;0.0015). In addition, abnormalities in both maternal serum β-hCG and AF-AFP predicted fetal death. The relative risk of adverse obstetric outcome was 10.667 (P = 0.0004; 95% confidence interval [CI]: 1.554-73.203) for β-hCG and 2.19 (P = 0.0256; 95% CI: 1.001 to 4.779), for AF-AFP. Maternal serum β-hCG and AF-AFP levels may preferentially identify those Turner syndrome pregnancies with the highest risk of fetal death.
Investigación clínica
The purpose of this work was to determine the expression of type Th1 cytokines: IL-2 and IFNgamma... more The purpose of this work was to determine the expression of type Th1 cytokines: IL-2 and IFNgamma, and Th2: IL-4 and IL-6, as well as TNF-alpha in patients with precancerous lesions of the uterine cervix and their relationship with the human papiloma virus (HPV). 30 patients with precancerous lesions (NIC 1: 70%, NIC 2: 16.7% and NIC 3: 1.3%) and 9 normal controls were studied. A clinical history, gynecological evaluation, cytology and an uterine biopsy were carried out in each patient and control. PCR was used for the diagnosis of HPV. IFN-gamma expression (positive cells/field) was increased in patients with NIC (5.06 +/- 4.7 vs 0 in the control group; p < 0.05). TNFa was a little higher in pathologycal tissues than in the controls (5.23 +/- 3.63 vs 1.55 +/- 2.65; p < 0.05). IL-2 was higher in pathologycal cases than in the controls (8.73 +/- 5.23 vs 0.33 +/- 1, p < 0.05). IL-4 were expressed in both, patients and controls (6.53 +/- 5.23 vs 5.77 +/- 7.32). IL-6 was also higher in patients (4.63 +/- 3.34 vs 0.77 +/- 2.33; p < 0.05). When the HPV status was considered, only IFN-gamma (p < 0.05) and IL-2 (p < 0.05) were significantly higher in HPV positive patients (n = 4) compared to controls. When HPV+ patients were compared with HPV- patients, only IFNgamma was significant (11.5 +/- 5 vs 4.07 +/- 3.8; p < 0.05). In conclusion, Type Th1 immune response prevails in patients with precancerous lesions, whether they are HPV positive or not.
Nefrología : publicación oficial de la Sociedad Española Nefrologia, 2007
Mycophenolate mofetil (MMF) is a purine synthesis inhibitor commonly used as immunosupresive agen... more Mycophenolate mofetil (MMF) is a purine synthesis inhibitor commonly used as immunosupresive agent in transplantation. Kidney grafts undergo more or less prolonged cold ischemia after harvesting which results in variable degrees of ischemia reperfusion injury. To determine whether the inhibition of early events of cellular infiltration may influence the severity of damage induced by ischemic acute renal failure, 45 Sprague Dawley rats were given MMF at a dose of 20mg/kg/day (MMF-rats) by gavage 2 days before (pre-MMF group, n=15) or after (post-MMF group, n=15) clamping the left renal artery for 40 minutes followed by rigt-sided nephrectomy. (control group, n=15) received vehicle. Serum Creatinine (Screat) was measured daily in all groups. On the 2nd post-ischemic day Screat was significantly lower (p=0.001) in pre-MMF group compared with post-MMF group and control group (4 +/- 2mg/dl post-MMF group vs 1.7 +/- 1.2 mg/dl pre-MMF group, control group 5+/-2, p< 0.05). Kidney biopsie...
Neurochemical research, 2003
The effect of melatonin (MLT) on the brain levels of tumor necrosis factor alpha (TNF-alpha) and ... more The effect of melatonin (MLT) on the brain levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in Venezuelan equine encephalomyelitis (VEE) virus infection was determined. Brain homogenates from mice inoculated with 10 LD50 of VEE virus, untreated or treated with 500 microg MLT/kg body weight were assayed by ELISA to measure the levels of TNF-alpha and IL-1beta. MLT was injected daily starting 3 days before and continuing to 7 days after virus inoculation. Infected mice treated with MLT showed decreased levels of TNF-alpha when compared to the untreated infected mice on days 1, 3, 4, and 5 postinoculation (P < 0.001). In contrast, IL-1beta levels increased from days 1 to 5 in the infected mice treated with MLT when compared with the untreated infected animals (P < 0.01). The results suggest that the protective effect of MLT on the VEE virus infection could be due, among other factors, to a decrease in TNF-alpha synthesis along with an increase in...