Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nerve growth factor, brain-derived neurotrophic factor, and other neurotrophic factors have been reported to have neuroprotective effects against global ischemia. To investigate whether the homodimer of platelet-derived growth factor B-chain (PDGF-BB) can protect neurons against focal temporary ischemia, PDGF-BB was administered to the rat brain for a prolonged period prior to, during, and after ischemia, since PDGF-BB protected rat neurons from global ischemia in our previous study. A total of 82 male Sprague-Dawley rats were used. Recombinant PDGF-BB, or saline was administered into the left neocortex via an implanted osmotic pump for 3 days (1.2 microg in total), 7 days (2 microgram or 4 microgram in total), or 14 days (4 microgram in total) pre-ischemia and 2 days post-ischemia. In an additional group, PDGF-BB (4 microgram in total) was administered for 14 days by osmotic pump and focal ischemia was induced after an additional 7-day interval following removal of the pump. Focal temporary ischemia was induced in the left MCA territory by bilateral CCA and MCA occlusion for 2 h. All rats were sacrificed 2 days after ischemia and the volume of cerebral infarct was analyzed using TTC staining. In a separate set of animals, regional cerebral blood flow (rCBF) was monitored by the hydrogen clearance method and laser Doppler flowmetry (LDF) of the neocortex after 14 days of intracerebral administration of PDGF-BB or saline. In the group receiving PDGF-BB (4 microgram in total) for 7 or 14 days pre-ischemia, there was a significant reduction of neocortical infarction compared to that in the control or saline-infused group. The size of cerebral infarct was smallest in the group that received PDGF-BB for 14 days, when ischemia was induced 7 days after removal of the pump. Regarding rCBF measurement, there were no significant differences in groups receiving PDGF-BB or saline infusion for 14 days. The potent neuroprotective effect of PDGF-BB on global ischemia was also demonstrated in the focal ischemia model. However, prolonged intracerebral infusion for 7 to 14 days was necessary to achieve a significant reduction of infarct volume. Neuroprotection was not due to increased collateral flow during ischemia.
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PMID:Induction of infarct tolerance by platelet-derived growth factor against reversible focal ischemia. 951 39

Molecular studies of giant cell arteritis indicate that T cells are recruited to the wall of medium-sized and large arteries, are activated locally, produce IL-2 and IFN-gamma, and regulate the activity of tissue-infiltrating macrophages. Downstream effects of T cell activation include the production of proinflammatory cytokines, metalloproteinases, and growth factors. Growth factors are instrumental in the process of intimal hyperplasia, leading to luminal occlusion and tissue ischemia. The amounts of IL-2, IFN-gamma, and the growth factor PDGF in the vascular lesions varies among patients and are correlated with differences in patterns of clinical manifestations. Giant cell arteritis complicated by cranial ischemia, such as anterior optic neuropathy or stroke, is characterized by high levels of IFN-gamma and PDGF. If the IFN-gamma-PDGF loop is less developed, fever and wasting can dominate the disease. Dominant production of IL-2 is associated with polymyalgia rheumatica. The finding of different inflammatory pathways translating into different clinical phenotypes may reflect differences in the contribution of the arterial wall. Alternative hypotheses include a role of multiple disease-inducing antigens with different tissue distributions or tropisms.
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PMID:Giant cell arteritis--a molecular approach to the multiple facets of the syndrome. 992 95

Nephrovasculopathies are an increasing cause of end-stage renal failure. Nephrosclerosis is a common finding in the hypertensive patient. However, genetic factors play a prominent role in its incidence. Nephrosclerosis is a common cause of early renal failure in blacks of African ancestry, as opposed to white Europeans, in whom hypertensive nephrosclerosis rarely and slowly leads to uremia. That primary hypertension is accompanied by arterionephrosclerosis and arteriolonephrosclerosis, by focal and segmental glomerulosclerosis leading to glomerular obsolescence and by interstitial fibrosis has been established for nearly a century. However, renal vascular lesions can be observed in animal models as well as in some humans, especially blacks, in the absence of, or preceding the onset of hypertension. This suggests that nephroangiosclerosis might stem from a genetic defect in the renal vascular bed, a defect closely associated with the hypertensive trait. Atherosclerotic renal artery stenosis is a major, potentially remediable cause of chronic renal failure, especially in whites. Its prevalence in the atherosclerotic population is in the order of 15 percent. This figure has obvious bearing in terms of health cost. Early diagnosis and treatment by angioplasty or surgery can preclude development to end-stage renal disease and maintenance hemodialysis, as renal atrophy due to chronic ischemia resulting from renal artery stenosis can be halted or partially reversed by revascularization before extensive fibrosis sets in. Finally, renal vascular lesions are commonly observed in the course of various nephropathies, even in the absence of hypertension. The relationship between fibrogenesis and these vascular lesions, which develop along with interstitial fibrosis and entail an unfavorable prognosis in various glomerulopathies, remains to be elucidated. This is especially the case for focal-segmental glomerulosclerosis, membranous glomerulopathy and IgA glomerulonephritis. The pathophysiology of renal fibrosis induced by ischemia is centered on increased generation of angiotensin II that is fibrogenic owing to interaction with endothelin 1, PDGF-BB and TGF-beta. These notions open perspectives toward pharmacologic means to retard or even prevent the development of such various ischemic conditions to end-stage renal failure.
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PMID:[Vascular mechanisms of renal fibrosis. Vasculonephropathies and arterial hypertension]. 1037 63

Various polypeptide growth factors are generally considered to be involved in the regulation of the nephrogenic process both after acute renal injury and during renal development. Because platelet-derived growth factor B-chain (PDGF-B) has been reported to be expressed in immature tubulus of the developing kidney, PDGF-B could play a role in the process of tubulogenesis. We examined the expression of PDGF-B and PDGF receptors alpha and beta and their localization in kidneys after ischemia/reperfusion injury. The mRNA expressions of PDGF-B, PDGFR-alpha, and PDGFR-beta were enhanced after injury. In the immunohistochemical analysis and/or in situ hybridization, PDGF-B and PDGFR-alpha, beta were expressed after reperfusion in the S3 segment of the proximal tubuli, where they were not expressed normally. The expressions of proliferating cell nuclear antigen and vimentin were concomitantly observed with PDGF-B and PDGFRs in the tubular cells of injured S3 segment at 48 hours after injury. Next, the inhibition of the PDGF-B/PDGFRs axis with either Trapidil or Ki6896, which was found to inhibit the phosphorylation of PDGFR-beta selectively, resulted in a rise of serum creatinine, higher mortality rate, abnormal regenerating process, and suppressed proliferation of tubular epithelial cells. These findings suggest that the PDGF-B/PDGFRs axis is involved in the proliferation of injured tubular cells and plays an important role in the regeneration of tubular cells from acute ischemic injury.
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PMID:Role of PDGF B-chain and PDGF receptors in rat tubular regeneration after acute injury. 1055 Mar 25

Adenosine inhibits growth of cardiac fibroblasts; however, the adenosine receptor subtype that mediates this antimitogenic effect remains undefined. Therefore, the goals of this study were to determine which adenosine receptor subtype mediates the antimitogenic effects of adenosine and to investigate the signal transduction mechanisms involved. In rat left ventricular cardiac fibroblasts, PDGF-BB (25 ng/mL) stimulated DNA synthesis ((3)H-thymidine incorporation), cellular proliferation (cell number), collagen synthesis ((3)H-proline incorporation), and MAP kinase activity. The adenosine receptor agonists 2-chloroadenosine and 5'-N-methylcarboxamidoadenosine, but not N(6)-cyclopentyladenosine, 4-aminobenzyl-5'-N-methylcarboxamidoadenosine, or CGS21680, inhibited the growth effects of PDGF-BB, an agonist profile consistent with an A(2B) receptor-mediated effect. The adenosine receptor antagonists KF17837 and 1,3-dipropyl-8-p-sulfophenylxanthine, but not 8-cyclopentyl-1,3-dipropylxanthine, blocked the growth-inhibitory effects of 2-chloroadenosine and 5'-N-methylcarboxamidoadenosine, an antagonist profile consistent with an A(2) receptor-mediated effect. Antisense, but not sense or scrambled, oligonucleotides to the A(2B) receptor stimulated basal and PDGF-induced DNA synthesis, cell proliferation, and collagen synthesis. Moreover, the growth-inhibitory effects of 2-chloroadenosine, 5'-N-methylcarboxamidoadenosine, and erythro-9-(2-hydroxy-3-nonyl) adenine plus iodotubericidin (inhibitors of adenosine deaminase and adenosine kinase, respectively) were abolished by antisense, but not scrambled or sense, oligonucleotides to the A(2B) receptor. Our findings strongly support the hypothesis that adenosine causes inhibition of CF growth by activating A(2B) receptors coupled to inhibition of MAP kinase activity. Thus, A(2B) receptors may play a critical role in regulating cardiac remodeling associated with CF proliferation. Pharmacologic or molecular biological activation of A(2B) receptors may prevent cardiac remodeling associated with hypertension, myocardial infarction, and myocardial reperfusion injury after ischemia.
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PMID:A(2b) receptors mediate the antimitogenic effects of adenosine in cardiac fibroblasts. 1123 Mar 62

Optimal medical treatment of ischemic diabetic ulcers is multifactorial. Infection is very common and it is necessary to distinguish between limb or life threatening infections and non-limb-threatening infections. The major pathogen associated with non-limb-threatening infection is staphylococcus aureus; oral antibiotics such as amoxicillin/clavulanate or clindamycin can be used. For severe infection, empiric antibiotic therapy is broader-spectrum covering staphylococci, streptococci, gram-negative bacilli and enterococci; intravenous administration is the rule. Duration of antibiotic therapy depends on severity and depth of infection, and on requirement of surgical debridment. Granulocyte colony-stimulating factor is a growth factor stimulating proliferation and function of neutrophils. As an adjunctive therapy for limb-threatening infections, it is associated with a lower rate of amputation. Increasing arterial perfusion if the patient is unsuitable for reconstructive surgery or angioplasty is desirable. Iloprost is an analogue of epoprostenol with effects on platelet aggregability and vasodilatation. It improves ulcer healing, decreases pain, slightly diminishes the rate of amputation. Systemic hyperbaric oxygen therapy can perhaps improve clinical outcome but additional research is needed to define the specific indications and benefits of this treatment modality. Local care is not rationalized and depends on local habits. Debridment is required. Non necrotic wounds can be covered by modern dressing (hydrophilic dressing, alginates, hydrocolloid). Necrotic wounds are dryed until surgical revascularization, or excised if they are limited and superficial. Pinch grafts are very useful for arterial ulcers. The place of topical growth factor like PDGF (platelet derived growth factor) and of living skin equivalents (dermagraft, apligraf) is not defined in ischaemic diabetic ulcers. Treatment of edema is necessary, because it retards or complicates healing. Inelastic bandages can be useful with good tolerance if ischemia is not critical. Pneumatic foot compression is under evaluation. Electric stimulation could be an adjuncting treatment, but with a problem of compliance. Reducing plantar pressure is always necessary.
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PMID:[Local care and medical treatment for ischemic diabetic ulcers]. 1223 32

We previously reported that the platelet-derived growth factor B-chain (PDGF-B)/PDGF receptor (PDGFR) axis is involved in tubular regeneration after ischemia/reperfusion injury of the kidney. In the present study, we examined the activation of Src tyrosine kinase, a crucially important signaling molecule for PDGFR, and assessed the role of Src in PDGF-B-dependent renal tubular regeneration afterischemia/reperfusion injury. Immunoblot using clone 28, a monoclonal antibody specific for the active form of Src kinases, demonstrated increased active Src expression in the injured rat kidney 6 hours after reperfusion with peak activation at 12 hours. In vitro kinase assay confirmed increased Src activity that concurred with PDGFR-beta activation as detected by the increment of receptor-phosphorylated tyrosine. Immunohistochemistry using clone 28 demonstrated that active Src was preferentially expressed in the S3 segment of the proximal tubule in reperfused kidney, where it is not normally expressed. This enhanced expression of active Src was co-localized with the increased PDGFR expression in the tubular cells that were undergoing cell proliferation cycle. Trapidil administration suppressed Src and PDGFR-beta activation in the reperfused kidney and resulted in deteriorated renal function. These findings suggest that active Src participates in PDGF-B-dependent regeneration of tubular cells from acute ischemic injury.
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PMID:Activation of Src kinase in platelet-derived growth factor-B-dependent tubular regeneration after acute ischemic renal injury. 1281 32

Therapeutic effects of combination of angiogenic growth factors for the treatment of ischemia after myocardial infarction are largely unknown. Plasmids expressing basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF-BB) or their combination with a 1:1 mass ratio were injected into hearts with 7-day-old myocardial infarction. Hearts were harvested after 1 and 4 weeks after gene transfer. The major findings in this chronic myocardial infarction model were that bFGF, PDGF-BB and their combination all had a more pronounced angiogenic effect on the arteriolar than the capillary level. bFGF stimulated both capillary and arteriolar growth while PDGF-BB preferentially stimulated arterioles. The combination increased the amount of both capillaries and arterioles and in addition gave rise to stable capillaries compared to single factor transfer but did not further enhance angiogenesis. No cardiovascular side effects were observed after gene transfer.
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PMID:Angiogenic effects of dual gene transfer of bFGF and PDGF-BB after myocardial infarction. 1498 20

Becaplermine gel (Regranex) is an hydrogel which contains 100 microg of Platelet Derived Growth Factor-BB (rhPDGF-BB) per gram. Regranex is presented in 15-gram multidose tubes. It has been approved as adjuvant treatment for neuropathic diabetic ulcerations of less than 5 cm2, extending into the subcutaneous tIssue, in the absence of ischemia, in conjunction with a standardised program of appropriate wound care, (control of infection, sharp debridement, provision of a moist environment and avoidance of pressure on the wound). PDGF-BB promotes cutaneous wound healing by increasing proliferation and migration of dermal fibroblasts and extracellular matrix deposition. PDGF also promotes chemotaxis of neutrophils, monocytes and smooth muscle cells in wounds. Topical application of rhPDGF-BB speeds wound healing and promotes granulation tIssue formation, synthesis of extracellular matrix and the inflammatory phase of the wound healing process in healthy and healing-impaired animal models. In clinical trials in humans, accelarated healing has been demonstrated in patients with lower extremity diabetic neuropathic ulcers and decubitus sores by increasing granulation tIssue formation and epithelialization. Local toxicity studies in humans were negative (repeated becaplermin gel application under occlusion to intact or abraded skin, dermal sensitization tests). Pharmacokinetic studies in humans have shown that systemic absorption after topical applications was minimal. In trials, systemic and local tolerance were excellent. Reported adverse effects were similar in incidence and in nature in all groups. The 0.01% Regranex gel is safe and easy to use, with single daily application. It is currently the only commercially available topical growth factor for use in cutaneous wound healing.
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PMID:[Becaplermin gel (Regranex gel)]. 1525 9

Hypoxia-ischemia (HI) causes injury to oligodendrocytes (OLs), cells which create the myelin sheath in the developing brain. OLs pass successively through progenitor and immature stages during differentiation into mature OLs. Only the OLs in the progenitors stage can express the platelet-derived growth factor-a receptor (PDGF-R(alpha)) so that its expression is one of the cellular markers of OL progenitors. Activation of PDGF-R(alpha) results in OL proliferation, but not OL differentiation. To study the response of OL progenitors after neonatal HI brain injury, we investigated the expression of PDGF-R(alpha) in a neonatal rat stroke model (combination of left common carotid artery ligation and exposure to 8% O2 for 2 h). In the injured cerebral cortex, PDGF-R(alpha) mRNA levels increased significantly (p<0.01) with a peak at 0.5 h after HI insult, and returned to baseline levels within 48 h post-injury. PDGF-R(alpha) protein levels increased significantly at 72-96 h (p<0.05) and then returned to basal levels. Immunohistochemistry showed clear staining of PDGF-R(alpha) only in the injured cerebral cortex at 72 h after HI insult. In contrast, no staining was observed in the cortex of sham-operated controls. These results indicate that the expression of PDGF-R(alpha) increases rapidly and transiently only in the injured cerebral cortex after HI insult and may play a protective role through modulating the glial differentiation under the condition of cellular damage in the developing brain.
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PMID:PDGF-alpha receptor expression following hypoxic-ischemic injury in the neonatal rat brain. 1534 68


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