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A Giaid

Publications and source records attributed to A Giaid.

At least 55 records · Page 3Linked to original sources
PubMed1997

Expression of nitric oxide synthases and GTP cyclohydrolase I in the ventilatory and limb muscles during endotoxemia.

Nitric oxide synthases (NOS) convert L-arginine to nitric oxide in the presence of tetrahydrobiopterin (BH4). Two constitutive isoforms of NOS exist in normal skeletal muscle fibers, however, the existence of a third, the inducible isoform (iNOS), has never been detected in these fibers in vivo. Therefore, we assessed the influence of in vivo endotoxemia on skeletal muscle expression of constitutive and inducible NOS isoforms and GTP cyclohydrolase I, the rate limiting enzyme of BH4 synthesis. Two groups of rats were infused i.p. either with E. coli endotoxin (20 mg/kg, LPS group) or saline (saline group). Animals were killed 6 h later and the ventilatory and limb muscles were quickly frozen. Endotoxin infusion elicited a significant rise in NOS activity of the diaphragm, intercostal, soleus and gastrocnemius muscles. Reverse transcription-polymerase chain reaction (RT-PCR) on muscle total RNA detected very low expression of iNOS and GTP cyclohydrolase I mRNA in the saline group, but significant upregulation of both enzymes was found in the ventilatory and limb muscles of the LPS group. Immunoblotting detected no iNOS protein in the saline group but a significant iNOS protein expression was found in the diaphragm, intercostal and soleus muscles and to a lesser extent, in the gastrocnemius of the LPS group. Endotoxemia was also associated with increased protein expression of constitutive NOS isoforms mainly in the diaphragm and to lesser extent in the intercostal, gastrocnemius and soleus muscles. We conclude that in vivo exposure to endotoxin leads to differential induction of both iNOS and GTP cyclohydrolase I in the ventilatory and limb muscles.

Animals↗
PubMed1996

Altered nonspecific lymphocyte cytotoxicity in bronchoalveolar lavage of lung transplant recipients: can it be useful in monitoring rejection or infection?

A reliable method for determining the adequacy of immunosuppression of the lung allograft and the absence of rejection or infection does not exist. The purpose of this study is to evaluate the potential role of bronchoalveolar lavage (BAL) in monitoring the adequacy of immunosuppression of lung allografts and in identifying the possible presence of acute rejection (AR) or infection. Thirty-one consecutive lung transplant recipients were subjected to bronchoscopy, transbronchial biopsy, and BAL either as routine surveillance or for decline in lung function (n=68 episodes: 27 normal, 17 infections, six grade IAR, 10 grade II-III AR, and eight obliterative bronchiolitis). Diagnosis was always confirmed histologically and by microbiological workup. Harvested cells underwent phenotypic analysis, and T lymphocytes were subjected to nonspecific lectin-dependent cell-mediated cytotoxicity (LDCMC) and natural killer cytotoxic assays. BAL from normal grafts predominantly contained macrophages (72.8+/-4.4%), with lower neutrophil (13.9+/-4.1%) and lymphocyte (13.2+/-2.2%) populations. Grade II-III AR and infection were associated with an increase in the percentage of neutrophils (43.3+/-8.3% and 33.2+/-3.6%, respectively, P=0.02). BAL of normal allografts contained T cells with low LDCMC (7.4+/-4.5%) and natural killer cytotoxicity (6.3+/-3.4%), whereas grade II-III AR was associated with a significant elevation in LDCMC (32.5+/-11.6%, P=0.019). Pulmonary infection, regardless of its type, was associated with significant elevation in BAL natural killer cytotoxicity (23.9+/-4.9%, P=0.033). Patients with obliterative bronchiolitis, on the other hand, had a mild elevation in the percentage of neutrophils and lymphocytes in BAL, which did not reach statistical significance. However, BAL T-cell LDCMC was significantly elevated (37.6+/-13.7%, P=0.019) compared with normal and infected allografts. We conclude that phenotypic and nonspecific cytotoxic T-cell analysis of BAL, when complimented with microbiological studies, may be useful in surveillance of lung transplant recipients and in determining whether allografts are likely to be quiescent, or possibly affected by acute/chronic rejection or infection, necessitating further definitive action.

Bronchoalveolar Lavage↗
PubMed1996

Expression of endothelin-1 in pancreatic tissue of patients with chronic pancreatitis.

Chronic pancreatitis is characterized by the presence of an inflammatory infiltrate, progressive destruction of acinar cells, and fibrosis. The finding that endothelin-1, an endothelium-derived peptide with vasoconstrictive and mitogenic properties, reduces pancreatic blood flow in normal rats suggested that the peptide may be associated with the reduced pancreatic flow seen in animal models of chronic pancreatitis and in the morphological abnormalities of the disease. The aim of this study was to investigate sites of endothelin-1 expression in the pancreas of normal subjects and patients with chronic pancreatitis. The techniques of immunohistochemistry, in situ hybridization, and Northern blotting were used. Endothelin-1-like immunoreactivity was localized predominantly to islet cells both in normal subjects and in patients with chronic pancreatitis. Semi-quantitative analyses of immunostaining showed that endothelin-1-like immunoreactivity in islet cells of patients with chronic pancreatitis was greater than in normal subjects. Co-localization studies with glucagon, insulin, somatostatin, and pancreatic polypeptide showed that endothelin-1-like immunoreactivity co-exists with glucagon and insulin. There was no apparent co-existence of endothelin-1-like immunoreactivity with somatostatin or pancreatic polypeptide. Endothelin-1 mRNA was expressed in sites similar to those of the immunostaining, as well as in vascular endothelial cells. Northern blot analysis showed an increase in the expression of endothelin-1 mRNA in the patient population. There was a significant correlation between intensity of endothelin-1 immunostaining and severity of fibrosis in the patients with chronic pancreatitis. These findings suggest that an elevation in local expression of endothelin-1 may be associated with the morphological and haemodynamic changes of chronic pancreatitis.

Adult↗
PubMed1996

Amelioration of pulmonary allograft injury by administering a second rinse solution.

OBJECTIVE: The use of rinse solutions before reperfusing liver allografts has been shown to reduce cell death in rats. Carolina rinse solution (an extracellular solution that contains antioxidants, vasodilators, and other substrates that help prevent ischemia-reperfusion injury) has also been shown to improve liver function clinically in liver transplant recipients. This pilot study evaluates the value of a second pulmonary artery flush before reperfusion of a lung graft. METHODS: Six groups of Sprague-Dawley rats (n = 6 each) were subjected to the following: Group 1 lungs were preserved with modified Euro-Collins solution followed by 24 hours of cold ischemia. Group 2 lungs were treated the same as group 1 but reperfused with blood. Group 3 lungs were preserved in Carolina rinse solution followed by 24 hours of cold ischemia. Group 4 lungs were treated the same as group 3 lungs and then reperfused with blood. Lungs in groups 5 and 6 were preserved with Euro-Collins solution, stored cold for 24 hours, and then rinsed with Euro-Collins or Carolina rinse solution, respectively, before reperfusion with blood. Lungs were subsequently stained with trypan blue solution for 5 minutes. Lung blocks were fixed and embedded in water-soluble methacrylate. Trypan blue--stained nuclei in nonviable endothelial cells and alveolar pneumocytes were counted in 10 different fields. RESULTS: Groups 1 and 3, preserved with Euro-Collins and Carolina rinse solutions for 24 hours but not reperfused with blood, had significantly more viable endothelial cells (groups 1 and 3 vs group 2, p < 0.0001; group 3 vs group 4, p < 0.02) and pneumocytes (group 1 vs groups 2 and 4, group 3 versus group 2, p < 0.0001; group 3 vs group 4; p < 0.035) than groups 2 and 4, which were subsequently reperfused with blood. Groups 5 and 6, which received a second rinse, also had significantly more viable endothelial cells (p < 0.0005) and pneumocytes (p < 0.0001) than control groups, which were not rinsed before reperfusion. CONCLUSIONS: We conclude that damage to pulmonary allografts resulting from prolonged ischemia is accentuated by reperfusion with blood. We also conclude that preservation with a single flush of Euro-Collins or Carolina rinse solution does not offer adequate protection, whereas a second rinse before reperfusion significantly decreases the number of damaged cells within the allograft.

Animals↗
PubMed1996

Alterations in pancreatic microcirculation and expression of endothelin-1 in a model of chronic pancreatitis.

Chronic pancreatitis (CP) is characterized by the presence of an inflammatory infiltrate with progressive destruction of acinar cells and fibrosis. The finding that endothelin-1 (ET-1), an endothelium-derived peptide having vasoconstrictive and mitogenic properties, reduces pancreatic blood flow (PBF) in normal rats suggested that the peptide may be associated with the reduced PBF seen in animal models of CP and with the morphological abnormalities of the disease. This study investigates changes in blood flow to the pancreas and other abdominal organs in a rat model of CP and compares ET-1 production in the pancreata of these rats and normal controls. CP was induced in male Wistar rats by the injection of oleic acid into the common bile/pancreatic duct. The radiolabeled microsphere technique was employed to measure blood flow to the pancreas, duodenum, liver, spleen, and kidneys. Immunohistochemistry was used to investigate the cellular production of ET-1. After 3 weeks, significant decreases were noted in body weight, pancreatic weight, and pancreatic DNA, amylase, and protein content in the animals with CP. PBF was reduced by 64% and duodenal blood flow by 80% relative to those in control animals. Hepatic and splenic blood flows were increased by 91 and 88%, respectively, compared to those in controls. A 50% decrease in renal blood flows were increased by 91 and 88%, respectively, compared to those in controls. A 50% decrease in renal blood flow was also seen in the experimental group after 3 weeks. Pancreata from animals with CP stained diffusely for ET-1 in the cytoplasm of vascular endothelial, acinar, and ductal cells. In the control pancreata, focal staining for ET-1 was observed only in acinar cells. This difference was significant in endothelial and ductal cells. There was weak staining of islet cells in both groups. The results suggest that elevation in local production of ET-1 may be associated with the morphological and hemodynamic changes of CP.

Animals↗
PubMed1996

Expression of nitric oxide synthase in the human nasal mucosa.

The nasal mucosa plays an important role in defense of the lung against harmful agents. It has been suggested that this is partly mediated by the production of nitric oxide (NO). We have investigated the localization of the messenger ribonucleic acids (MRNAs) for human endothelial NO synthase (Type III NOS) and inducible NO synthase (Type II NOS) and the immunoreactivities of these enzymes in human nasal mucosa by immunohistochemistry, in situ hybridization, and reduced nicotinamide adenine diphosphate (NADPH) diaphorase histochemistry. Inferior nasal turbinates were obtained from 27 patients at the time of surgery for local disease. Strong immunostaining for Type III NOS was localized to vascular endothelium, surface epithelium, and submucosal glands in all subjects. Moderate immunostaining for Type II NOS was seen in surface epithelium; glandular, inflammatory, and vascular endothelial cells; and smooth-muscle cells in the specimens from patients with chronic rhinitis only. In situ hybridization showed expression of the mRNA for Type III NOS in similar sites to those shown by immunohistochemistry, whereas the mRNA for Type II NOS was predominantly localized to inflammatory cells. The sites of NOS expression were further confirmed by NADPH histochemical staining. These findings demonstrate the cellular expression of NOS in the human nasal mucosa and suggest a possible role for Types II and III NO synthase in the regulation of blood flow, nasal secretion, and ciliary movement in health and disease.

Adult↗
PubMed1996

Co-expression of endothelin-1 and endothelin-converting enzyme-1 in patients with chronic rhinitis.

Several studies have suggested an important role for endothelin in the pathophysiology of the upper and lower respiratory tract. In the present study, we have investigated the localization of endothelin-1 (ET-1) and endothelin-converting enzyme-1 (ECE-1) messenger RNAs(mRNAs) and immunoreactivities in the human nasal mucosa by immunohistochemistry and in situ hybridization. Inferior turbinates were obtained from 32 patients at surgery. Histopathologic examination of nasal biopsy specimens revealed that 17 patients had chronic inflammation and 15 patients had normal mucosa. Immunostaining for ET-1 and ECE-1 was seen in the surface epithelium, endothelial cells, submucosal glands, and infrequently in vascular smooth muscle cells, in all subjects. There was significantly more staining for ET-1 and ECE-1 in nasal glands and inflammatory cells in patients with chronic inflammation than in those with normal nasal mucosa. In patients with chronic inflammation, strong immunoreactivity for ECE-1 was seen over inflammatory cells. In situ hybridization showed abundant expression of ET-1 and ECE-1 mRNAs over the surface epithelium, glands, vessels, and inflammatory cells. Both immunohistochemistry and in situ hybridization demostrated the expression of ET-1 and ECE-1 immunoreactivities and mRNAs in similar sites, and also independently. The present findings demonstrate the co-expression of ET-1 and its converting enzyme in the human nasal mucosa and suggest a possible role for the endothelin system in the pathogenesis of chronic rhinitis.

Adult↗
PubMed1996

Ontogeny of growth hormone receptors in human tissues: an immunohistochemical study.

Both experimental and clinical studies suggest that human GH (hGH) may have a functional role during early stages in human development. To determine when receptors for hGH appear in specific target cells, we carried out an immunohistochemical analysis of six tissues obtained from 20 fetuses (8.5-20 weeks fetal age [FA]), two term infants, one 11-yr-old male, and one 43-yr-old male. Liver parenchymal and bile duct cells showed specific staining from the earliest FA examined (8.5 weeks); in fetal liver, the intensity of the immunoreaction was greatest in hepatocytes surrounding the central veins and portal triads, whereas the numerous hematopoietic cells exhibited little to no immunostaining. Kidney tissues also showed positive localization at 8.5-9 weeks FA. By 13 weeks, epithelial cells of most tubules were immunoreactive, with medullary tubules showing stronger staining than those in the cortex, whereas visceral epithelial cells of glomeruli were weakly positive; metanephrogenic blastemal cells were negative. A similar immunostaining pattern was observed in midgestation and postnatal kidneys, except that glomerular staining was lost by 19 weeks FA. Fetal zone cells of fetal adrenals showed weak immunostaining beginning at 13-14 weeks; glomerulosa cells stained intensely in the postnatal adrenal. Epithelial crypt cells in both small and large intestine immunostained beginning at 19-20 weeks; a similar pattern was observed in postnatal sections. Dermal fibroblasts and skeletal muscle of abdominal skin were positive from 8.5 weeks. Epidermal cells first showed immunostaining at 13-14 weeks; germinal layer cells showed the most intense reaction until 19-20 weeks, when the staining pattern became uneven throughout the epidermal layers. Epithelial cells in hair follicles and sebaceous glands were positive from 13-14 weeks; by 19-20 weeks, these cells were the most intensely immunostained in skin sections. Lung tissue was negative from 8.5-20 weeks, as well as postnatally. Vascular endothelial and smooth muscle cells routinely stained from 8.5 weeks FA in all tissues examined. We conclude that immunoreactive hGH receptors can be identified in early fetal, as well as postnatal, tissues and that the pattern of cellular immunostaining develops gradually throughout gestation in a very tissue-specific manner.

Adult↗
PubMed1995

Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension is characterized by abnormal thickening of the pulmonary arteries and increased pulmonary vascular resistance. Nitric oxide is a potent endothelium-derived vasorelaxant substance and an inhibitor of smooth-muscle-cell growth. Nitric oxide is produced in various cell types by the action of an enzyme, nitric oxide synthase. We compared the expression of endothelial nitric oxide synthase in the lungs of control subjects with that in the lungs of patients with pulmonary hypertension. METHODS: We investigated the expression of endothelial nitric oxide synthase by histochemical and immunohistochemical analysis, in situ hybridization, and Northern blot analysis in the lungs of 22 patients with plexogenic pulmonary arteriopathy (arteriopathy of grades 4 through 6), 24 patients with secondary pulmonary hypertension (arteriopathy of grades 1 through 3), and 23 control subjects. RESULTS: In the lungs of the control subjects, nitric oxide synthase was expressed at a high level in the vascular endothelium of all types of vessels and in the pulmonary epithelium. In contrast, little or no expression of the enzyme was found in the vascular endothelium of pulmonary arteries with severe histologic abnormalities (i.e., plexiform lesions) in patients with pulmonary hypertension. The intensity of the enzyme immunoreactivity correlated inversely with the severity of histologic changes. There was an inverse correlation between the arterial expression of the enzyme and total pulmonary resistance in patients with plexogenic pulmonary arteriopathy (r = -0.766, P = 0.004). CONCLUSIONS: Pulmonary hypertension is associated with diminished expression of endothelial nitric oxide synthase. It is possible that decreased expression of nitric oxide synthase may contribute to pulmonary vasoconstriction and to the excessive growth of the tunica media observed in this disease.

Adult↗
PubMed1995

Evidence for a role of endothelin 1 and protein kinase C in nitroglycerin tolerance.

We sought to examine mechanisms responsible for increased vasoconstriction that occurs during development of nitroglycerin tolerance. Rabbits were treated for 3 days with nitroglycerin patches (0.4 mg/hr), and their aortic segments were studied in organ chambers. This treatment resulted in attenuated in vitro relaxations to nitroglycerin and increased contractile sensitivity to angiotensin II, serotonin, phenylephrine, KCl, and a direct activator of protein kinase C, the phorbol ester phorbol 12,13-dibutyrate. The protein kinase C antagonists calphostin C (100 nM) and staurosporine (10 nM) corrected the hypersensitivity to constrictors in tolerant vessels, yet had minimal effects on constrictions in control vessels. Paradoxically, constrictions caused by endothelin 1 were decreased in nitrate-tolerant vessels. Immunocytochemical analysis revealed intense endothelin 1-like and big endothelin 1-like immunoreactivity in the media of nitroglycerin-tolerant but not of control aortas. The enhanced vasoconstriction to angiotensin II, serotonin, KCl, and phenylephrine could be mimicked in normal vessels by addition of subthreshold concentrations of endothelin 1, and this effect was prevented by calphostin C. We propose that increased autocrine production of endothelin 1 in nitrate tolerance sensitizes vascular smooth muscle to a variety of vasoconstrictors through a protein kinase C-mediated mechanism.

Alkaloids↗
PubMed1995

Endothelin-1 immunoreactivity and mRNA in the transplanted human heart.

Endothelin-1 (ET-1) is a 21-residue peptide produced by endothelial cells and possesses a wide range of biological activities, including vasoconstriction, mitogenesis, and inotropic effects on the heart. The aim of the present study was to determine the cellular localization of ET-1 immunoreactivity and mRNA in routine endomyocardial biopsy specimens of transplanted human hearts, and to correlate the findings with the associated histological changes. Multiple-step paraffin sections of 72 biopsy samples were immunostained with antiserum to ET-1 and von Willebrand factor (factor VIII) using the avidin-biotin-peroxidase complex method. ET-1 immunoreactivity was localized to vascular and endocardial endothelial cells, as well as to cardiomyocytes. The pattern of endothelial cell immunostaining with the ET-1 antiserum was similar to that of factor VIII. Previous biopsy sites and areas of granulation tissue appeared to have greater ET-1 immunoreactivity, particularly in sections immunostained with the ET-1 antiserum. There was a significant correlation between the presence of ET-1 immunoreactivity and fibrosis or granulation tissue in the biopsy specimens (P < 0.03). There was no correlation between ET-1 immunoreactivity and the presence of cellular infiltrate, definitive rejection, or Quilty effect. In situ hybridization with radiolabeled RNA probes revealed expression of ET-1 mRNA in endothelial cells and myocytes, also in association with granulation tissue and fibrosis. No cellular reactivity was present in control sections stained with the ET-1 antiserum preadsorped with its synthetic peptide. The findings suggests a possible role for ET-1 in vascular regeneration and angiogenesis following myocardial injury.

Biopsy↗
PubMed1995

Alterations in bronchoalveolar lavage and plasma endothelin-1 levels early after lung transplantation.

A temporary increase in pulmonary vascular resistance is observed during the first 24 hr following lung allotransplantation. We hypothesized that such early vascular changes are secondary to endothelial injury by ischemia-reperfusion, and that this may be mediated by an increased pulmonary endothelin-1 production/release. To test this hypothesis, radioimmunoassay was used to analyze endothelin-1 levels in bronchoalveolar lavage and plasma taken before surgery and at 1 hr, 4 hr, 24 hr, and 1 week after transplantation. The study was carried out on 2 groups of mongrel dogs. One group was subjected to left single-lung allotransplantation and the other to autotransplantation. Endothelin-1 levels in the bronchoalveolar lavage samples from the lung allografts were significantly increased at 1 (0.70 +/- 0.18 pg/ml) and 4 (1.84 +/- 0.65 pg/ml) hr after transplantation compared with the preoperative value (0.14 +/- 0.05 pg/ml), and declined at 24 (0.85 +/- 0.84 pg/ml) hr after transplantation. Similarly, plasma endothelin-1 levels in the allografts were significantly increased at 1 (2.0 +/- 0.80 pg/ml) and 4 (2.0 +/- 0.71 pg/ml) hr after transplant when compared with preoperative levels (0.54 +/- 0.09 pg/ml). Plasma endothelin-1 levels, however, remained significantly high after 24 hr (1.4 +/- 0.4 pg/ml; P < 0.007) and decreased after 1 week after transplant (0.89 +/- 0.32 pg/ml). On the other hand, endothelin-1 levels in bronchoalveolar lavage from the autograft group remained relatively unchanged; however, plasma levels showed a significant increase at 4 hr (6.6 +/- 1.8 pg/ml) after transplantation compared with preoperative levels (2.8 +/- 0.38 pg/ml). Elevation of endothelin-1 levels early after lung transplantation may play an important role in early high pulmonary vascular resistance and temporary graft dysfunction.

Airway Resistance↗
PubMed1995

Increased in vivo expression and production of endothelin-1 by porcine cardiomyocytes subjected to ischemia.

Circulating levels of the endothelium-derived vasoconstrictor peptide endothelin-1 (ET-1) are increased in association with myocardial ischemia and infarction. The present study investigates whether ET-1 is synthesized and produced locally in the ischemic heart. Sixteen pigs were divided into three groups. In the first group, the left anterior descending coronary artery was occluded for 90 minutes, followed by 150 minutes of reperfusion (group A, n = 8). Two additional groups were subjected to 90 minutes (group B, n = 4) or 240 minutes (group C, n = 4) of ischemia without reperfusion. Biopsies from the nonischemic and ischemic myocardium were rapidly obtained from the beating heart and subsequently examined by Northern blot, in situ hybridization, and immunohistochemistry. Arterial plasma ET-1 was measured before ischemia and at the end of the experiments. Northern blot revealed a twofold increase in ET-1 mRNA in the ischemic myocardium compared with the nonischemic myocardium. In situ hybridization showed a considerable increase in ET-1 mRNA over the ischemic cardiomyocytes. Substantial ET-1-like immunoreactivity (ET-1-ir) was detected in cardiomyocytes in the ischemic region. In contrast, little or no ET-1-ir or mRNA was detected in nonischemic cardiomyocytes. Both in the ischemic and nonischemic regions, little ET-1-ir was detected in vascular endothelial cells or vascular smooth muscle cells. There was no difference in the intensity and distribution of ET-1 mRNA expression or ET-1-ir among experimental groups A, B, and C. Arterial plasma ET-1 was increased only in group A, the reperfused group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Cytokine interleukin-2, tumor necrosis factor-alpha, and interferon-gamma release after ischemia/reperfusion injury in a novel lung autograft animal model.

Previously, we have reported an increase in the cytokines interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) early after left lung allotransplantation in dogs. The purpose of this study was to develop a novel model of canine lung autotransplantation and to observe whether ischemia/reperfusion injury alone (in the absence of an allogenic stimulus) would result in this cytokine release as seen in the allograft. Thus, using this model, early changes in cellular and cytokine composition in the lung autograft were monitored through the use of bronchoalveolar lavage (BAL) and plasma. The effects of ischemia/reperfusion injury on lung histology and major histocompatibility class II (MHC II) antigen expression were also observed. Ten mongrel dogs were subjected to left lung autotransplantation. Lungs were stored cold for 4 h, with a warm ischemic time of 1 h. BAL, blood, and biopsy specimens were taken preoperatively and 1 h, 4 h, 24 h, and 1 wk postoperatively. The mean BAL IL-2 levels significantly rose from a preoperative value of 150 +/- 19 pg/ml to 246 +/- 67 pg/ml 4 h after transplantation (p < 0.05), decreasing to preoperative levels after 24 h (128 +/- 54 pg/ml). Plasma levels of IL-2 did not change from preoperative values. In contrast to IL-2, TNF-alpha and IFN-gamma did not change in either BAL or plasma of the autograft.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Plasma endothelin-1 levels in human lung transplant recipients.

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelial cells and is believed to play an important role in the pathophysiology of the pulmonary vasculature. We have investigated the early changes in ET-1 plasma levels in lung transplant recipients at various intervals before and after isolated lung transplantation. The mean plasma ET-1 level immediately before transplantation was 0.8 +/- 0.1 pg/ml. This was significantly increased to 2.6 +/- 0.5 pg/ml shortly after unclamping and vascular reperfusion of the allograft, and remained high 4 h (2.3 +/- 0.5 pg/ml), 6 h (2.4 +/- 0.6 pg/ml), and 12 h (1.7 +/- 0.3 pg/ml) after transplantation. Thereafter, the level of ET-1 started to decline, reaching 1.3 +/- 0.3 pg/ml 24 h and 0.9 +/- 0.3 pg/ml 1 week after transplantation. This early increase in ET-1 plasma level is consistent with our observation of alterations in pulmonary vascular resistance, pulmonary artery pressure and cardiac output early after transplantation. These findings demonstrate that an increase in plasma ET-1 levels shortly after lung transplantation may have a detrimental effect during the postoperative course early after transplantation.

Blood Pressure↗
PubMed1994

Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice.

Endothelins act on two subtypes of G protein-coupled receptors, termed endothelin-A and endothelin-B receptors. We report a targeted disruption of the mouse endothelin-B receptor (EDNRB) gene that results in aganglionic megacolon associated with coat color spotting, resembling a hereditary syndrome of mice, humans, and other mammalian species. Piebald-lethal (sl) mice exhibit a recessive phenotype identical to that of the EDNRB knockout mice. In crossbreeding studies, the two mutations show no complementation. Southern blotting revealed a deletion encompassing the entire EDNRB gene in the sl chromosome. A milder allele, piebald (s), which produces coat color spotting only, expresses low levels of structurally intact EDNRB mRNA and protein. These findings indicate an essential role for EDNRB in the development of two neural crest-derived cell lineages, myenteric ganglion neurons and epidermal melanocytes. We postulate that defects in the human EDNRB gene cause a hereditary form of Hirschsprung's disease that has recently been mapped to human chromosome 13, in which EDNRB is located.

Animals↗
PubMed1994

Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons.

Defects in the gene encoding the endothelin-B receptor produce aganglionic megacolon and pigmentary disorders in mice and humans. We report that a targeted disruption of the mouse endothelin-3 ligand (EDN3) gene produces a similar recessive phenotype of megacolon and coat color spotting. A natural recessive mutation that results in the same developmental defects in mice, lethal spotting (ls), failed to complement the targeted EDN3 allele. The ls mice carry a point mutation of the EDN3 gene, which replaces the Arg residue at the C-terminus of the inactive intermediate big EDN3 with a Trp residue. This mutation prevents the proteolytic activation of big EDN3 by ECE-1. These findings indicate that interaction of EDN3 with the endothelin-B receptor is essential in the development of neural crest-derived cell lineages. We postulate that defects in the human EDN3 gene may cause Hirschsprung's disease.

Amino Acid Sequence↗