Biomedical subjects

H Wei

Publications and source records attributed to H Wei.

At least 19 recordsLinked to original sources

PubMed2006

Alpha-V-dependent outside-in signaling is required for the regulation of CD44 surface expression, MMP-2 secretion, and cell migration by osteopontin in human melanoma cells.

The level of integrin alpha(v)beta3 and its ligand osteopontin (OPN) has been directly correlated to tumorigenicity of melanoma and other cancer cells. We have previously shown an increase in pp(60c-Src) kinase activity associated with integrin alpha(v)beta3 in melanoma cells (M21) treated with soluble OPN. pp(60c-Src) kinase activity was not observed in melanoma cells expressing alpha(v) that lacks the cytoplasmic domain (alpha(v)995). Results of the current study demonstrate that the amino acid sequence '995RPPQEEQERE1004' in the beta-turn of alpha(v) chain is required for the interaction of pp(60c-Src). Our results suggest that the beta-turn of alpha(v) chain may be indispensable for alpha(v)-associated signaling complex formation and outside-in signaling. To further analyze the alpha(v)beta3 signaling in melanoma cells, we over expressed OPN in M21 cells (M21/OPN). CD44 surface expression and MMP-2 activity in the conditioned medium were increased to a greater extent in M21/OPN cells as compared with M21 or alpha(v)995 cells. Also, M21/OPN cells exhibit increased motility, which is markedly reduced upon treatment with inhibitors to alpha(v) and MMP-2. Our findings suggest that the increase in MMP-2 activity is integrin-dependent as MMP-2 activity is reduced in cells treated with an inhibitor to alpha(v) or in alpha(v)995 cells expressing mutant alpha(v).

Actins↗

PubMed2006

The differential effects of low dose and high dose concanavalin A on cytokine profile and their importance in liver injury.

OBJECTIVE: Intravenous injection of concanavalin A (Con A) can cause mice to suffer from acute liver failure in a dose dependent manner and little is known about the difference between the high dose and the low dose of Con A regarding the immune response they initiate. The aim of this study was to analyze whether differential effects exist between the low dose and high dose of concanavalin A on the intrahepatic immune system and their importance in the development of liver injury. MATERIALS AND METHODS: A high dose of Con A (15 microg/g) was injected intravenously to induce murine hepatitis. A low dose of Con A (3 microg/g) was injected intravenously 12 h before the injection of the high dose of Con A (15 microg/g). Liver injury was evaluated by serum transaminase assay and H&E staining. Serum cytokine concentrations were determined by enzyme-linked immunosorbent assay (ELISA), intrahepatic cytokine and Fas mRNA levels by reverse transcriptase polymerase chain reaction. Intracellular cytokine expression and FasL expression were analyzed by flow cytometry and Fas protein expression in hepatocytes by Western-blotting. Intrahepatic apoptosis was evaluated by terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL). RESULTS: Low dose Con A injection induced a distinct cytokine expression profile, characterized by a preferentially elevated serum IL-6 at the early stage of stimulation, whereas high dose Con A injection provoked significant elevation of various cytokines involved in Con A-induced hepatitis. Pretreatment with a low, nonhepatoxic dose of Con A (3 microg/g) significantly decreased production of proinflammatory cytokines induced by the high dose Con A (15 microg/g). Furthermore, low dose Con A pretreatment could significantly decrease the serum levels of transaminases and liver necrosis induced by high dose of Con A. The intrahepatic Fas expression was also apparently reduced, accompanied by a decrease in hepatocyte apoptosis. CONCLUSION: Low dose Con A stimulation induced a different cytokine profile from high dose Con A stimulation resulting in differential importance in the development of liver injury.

Animals↗

PubMed2006

Advantages of C2 monitoring to avoid acute rejection in pediatric heart transplant recipients.

BACKGROUND: Inadequate cyclosporine (CsA) blood levels are a major risk factor for acute rejection in transplant recipients. The CsA trough level (C0 level) measured just before the next dose is commonly used to adjust the oral dosage. However, the 2-hour post-CsA dose concentration (C2 level) is favored as the best single-point correlate of CsA area-under-the-curve concentration and may better reflect the immunosuppressive effect of CsA. Because an adequate C2 level has not yet been defined, this study was performed to assess the value of C2 monitoring for the prevention of acute rejection and to define target levels in pediatric heart transplant recipients. METHODS: C2 levels were assessed in 50 pediatric heart transplant patients with oral CsA therapy and compared with trough C0 levels using full blood sampling, mass spectrometry and a blinded analysis. Acute graft rejection was detected using intramyocardial electrocardiogram (IMEG) and serial conventional and tissue Doppler echocardiography (TDE). Rejection was confirmed or excluded by endomyocardial biopsy. RESULTS: C2 and not C0 levels were significantly reduced in patients with acute graft rejection (ISHLT Grade > or =2). Patients with a C2 level <600 ng/ml had a significantly higher risk of developing acute rejection (100% sensitivity and 82% specificity). Patients with impaired CsA absorption were identified with C2 monitoring and switched to another calcineurin inhibitor. CONCLUSIONS: Monitoring of the C2 rather than the C0 level better reflects immunosuppressive efficiency and identifies patients at increased risk of acute rejection. A C2 level of >600 ng/ml should be the target to prevent acute rejection.

Adolescent↗

PubMed2005

The contribution of peripheral 5-hydroxytryptamine2A receptor to carrageenan-evoked hyperalgesia, inflammation and spinal Fos protein expression in the rat.

The present study was conducted to test the hypothesis that the peripheral 5-hydroxytryptamine (5-HT)2A receptor is involved in inflammatory hyperalgesia and production of noxious stimulus-induced neuronal activity at the level of the spinal cord dorsal horn. Intraplantar (i.pl.) injection of carrageenan dramatically reduced paw withdrawal latency to noxious heat (47 degrees C) and caused paw swelling. Pretreatment with ketanserin, a selective antagonist of 5-HT2A receptor, in the hindpaw produced dose-dependent inhibition of the hyperalgesia (0.5, 3 and 5 mug; i.pl.) with full relief at 5 mug. The drug also moderately reduced carrageenan-induced paw swelling in a dose-dependent manner. Carrageenan induced conspicuous expression of c-fos-like immunoreactivity (FLI) in the spinal dorsal horn of segments L4-5. Ketanserin (5 mug) markedly reduced carrageenan-induced FLI in all laminae of the dorsal horn. However, blockade of peripheral 5-HT1A receptors by (N-2-[4-(2-methoxyphenyl-1-piperazinyl] ethyl]-N-2-pyridinylcyclohexanecarboxamide at maximally effective doses (30 and 100 mug; i.pl.) did not alter carrageenan-induced hyperalgesia, edema or expression of FLI. The present study provided evidence at cellular level that the peripheral 5-HT2A receptor is preferentially involved in the development of thermal hyperalgesia in the carrageenan model of inflammation.

Animals↗

PubMed2005

Protracted lithium treatment protects against the ER stress elicited by thapsigargin in rat PC12 cells: roles of intracellular calcium, GRP78 and Bcl-2.

We investigated the cytoprotective effects of lithium, the mood-stabilizer, on thapsigargin-induced stress on the endoplasmic reticulum (ER) in rat PC12 cells. Protracted lithium pretreatment of PC12 cells elicited cytoprotection against thapsigargin-induced cytotoxicity. Lithium protection was concurrent with inhibition of thapsigargin-induced intracellular calcium increase and with elevated expression of the molecular chaperone GRP78. Moreover, lithium pretreatment upregulated the antiapoptotic protein Bcl-2, and blocked Bcl-2 downregulation elicited by thapsigargin. Prior to the induction of GRP78, lithium treatment alone increased the expression of c-Fos whose induction by ER stress is necessary for GRP78 induction. Curcumin, an inhibitor of transcription factor AP-1, blocked lithium cytoprotection against thapsigargin cytotoxicity. Thus, the induction of GRP78 and Bcl-2, and activation of AP-1 likely contribute to lithium-induced protection against cytotoxicity resulting from ER stress. Additionally, thapsigargin-induced cytotoxicity was suppressed by pretreatment with another mood-stabilizer, valproate, indicating that cytoprotection against ER stress is a common action of mood-stabilizing drugs.

Animals↗

PubMed2005

Activation and function of hepatic NK cells in hepatitis B infection: an underinvestigated innate immune response.

Natural killer (NK) cells are abundant in the normal liver, accounting for around one-third of intrahepatic lymphocytes and are important in the defence against hepatitis B virus (HBV) infection as innate immune responses. In this review, we discuss the mechanisms of hepatic NK cell activity against HBV. Whether directly activated by HBV infection or indirectly activated by other lymphocytes such as NKT cells or antigen-presenting cells (APCs), hepatic NK cells exert their anti-viral functions by natural cytotoxicity and production of high levels of cytokines. However, activated NK cells play an important role in regulating adaptive immune responses by interaction with other lymphocytes such as T, B and APCs. In addition, NK cells may contribute to the lymphocyte-mediated liver injury during HBV infection that was previously considered to be mediated only by CD8+ T cells or/and NKT cells.

Animals↗

PubMed2004

Short-term lithium treatment promotes neuronal survival and proliferation in rat striatum infused with quinolinic acid, an excitotoxic model of Huntington's disease.

We assessed the ability of lithium to reduce neurodegeneration and to stimulate cell proliferation in a rat model of Huntington's disease in which quinolinic acid (QA) was unilaterally infused into the striatum. LiCl (0.5-3.0 mEq/kg) was injected subcutaneously 24 h before and 1 h after QA infusion. At 7 days after QA injection, lithium significantly diminished the loss of neurons immunostained for Neuronal Nuclei (NeuN) in the injured striatum, but failed to prevent the reduction of NADPH-diaphorase-positive striatal interneurons. Lithium also reduced the number of neurons showing DNA damage or activated caspase-3. This neuroprotection was associated with an upregulation of Bcl-2 protein levels in the striatal tissue and an increase in the number and density of Bcl-2 immunostaining in striatal neurons. Bromodeoxyuridinie (BrdU) labeling in the lithium-treated injured striatum revealed the presence of large numbers of proliferating cells near the QA-injection site, with a reduction of BrdU-labeled cells in the subventricular zone (SVZ). All BrdU-labeled cells in the SVZ and the majority of BrdU-labeled cells near the QA-injection site were negative for either NeuN or glial fibrillary acidic protein (GFAP), suggesting that they are undifferentiated progenitor cells. However, a small number of BrdU-positive cells found in the QA-injected and lithium-treated striatum site were positive for either NeuN or GFAP. Our results suggest that lithium is neuroprotective in the QA-injection model of Huntington's disease not only due to its ability to inhibit apoptosis but also because it can stimulate neuronal and astroglial progenitor proliferation in the QA-injected striatum or their migration from the SVZ.

Animals↗

PubMed2003

[Effect of transforming growth factor beta 2 on phagocytosis in cultured bovine trabecular meshwork cells].

AIM: This study was performed to investigate the effect of transforming growth factor beta 2 (TGF-beta 2) on phagocytosis in bovine trabecular meshwork cells in vitro. METHODS: After cultured bovine trabecular meshwork cells were treated for 24 h with 0 ng/ml (control), 0.32 ng/ml, 1 ng/ml, and 3.2 ng/ml TGF-beta 2, latex beads were added to the incubation medium, and the numbers of latex beads in 20 adjacent cells were then counted under a microscope after treatment with Wright's stain. RESULTS: The average numbers of latex beads in the trabecular meshwork cells treated with TGF-beta 2 of different concentrations were 53.1+/-1.7 beads/cell, 56.4+/-2.9 beads/cell, and 77.9+/-6.5 beads/cell, respectively, compared to 45.5+/-3.3 beads/cell in the nontreated control group. Thus, TGF-beta 2 significantly increased the numbers of latex beads phagocytosed by cultured bovine trabecular meshwork cells in a dose-dependent manner. CONCLUSION: TGF-beta 2 can promote the phagocytosis of bovine trabecular meshwork cells in vitro. It may be involved in the reduced cellularity of the trabecular meshwork in patients with primary open angle glaucoma by promoting the phagocytosis of these cells.

Animals↗

PubMed2003

Clinical study on liposomal amphotericin B (Ambisome) in deep fungal infections in China.

Ambisome (L-Amb) was used to treat nine cases of meningitis or menigoencephalitis by Cryptococcus neoformans and 28 cases of other deep fungal infections. A retrospective study on conventional amphotericin B (C-Amb) was performed as the control. A series of indices was observed including curative effect, fungal clearance rate, course of treatment, daily dose, cumulative dose and adverse effects. Nine cases of cryptococcal meningitis or menigoencephalitis treated with Ambisome were clinically cured with an effective rate of 100%, within a mean course of 50 days, which was shorter than that of C-Amb, by a mean cumulative dose of 1807.2 mg, which was not statistically significant in comparison with C-Amb. Fungal clearance rate on the second month of treatment was 89% with Ambisome, which was higher than that of C-Amb. Twenty-eight cases of other deep fungal infections treated with Ambisome were clinically cured with an effective rate of 92%, within a mean course of 19.3 days, by a mean cumulative dose of 907.5 mg, and fungal clearance rate on the second and third month was 75 and 92%, respectively. The adverse effects by Ambisome decreased evidently compared with those by C-Amb.

Adolescent↗

PubMed2003

Both stress experience and age determine the impairment or enhancement effect of stress on spatial memory retrieval.

It has been documented that stress or glucocorticoids have conflicting effects on memory under different conditions. However, it is not fully understood why stress can either impair or enhance memory. Here, we have examined the performance of six age groups of Wistar rats in a water maze spatial task to evaluate the effects of stress under different conditions. We found that the impairment or enhancement effect of an 'elevated platform' (EP) stress on memory was dependent on previous stress experience and on age. EP stress impaired memory retrieval in water maze naive animals, but enhanced rather than impaired memory retrieval in young water maze stress-experienced animals. Furthermore, exogenously applied corticosterone or foot shock stress before water maze training prevented the impairment of memory retrieval that should be induced by treatment with corticosterone or foot shock before the 'probe trial'. Again, memory retrieval was enhanced in young animals under these conditions, and this enhancement can be prevented by the glucocorticoid receptor antagonist RU 38486. Thus, glucocorticoid receptor activation not only induced impairment of memory but also increased the capacity of young animals to overcome a later stress. The present findings suggest that the effect of stress on memory can be switched from impairment to enhancement dependent on both stress experience and age.

Aging↗

PubMed2002

Expression of PTHrP and its cognate receptor in the rheumatoid synovial microcirculation.

Parathyroid hormone-related protein (PTHrP), a multifunctional peptide that acts as a vasodilator as well as possible regulator of vascular development, is produced in increased amounts in the rheumatoid synovium. To understand whether PTHrP can contribute to the development and function of the rheumatoid microcirculation, studies were undertaken to identify and compare vascular sites of expression of PTHrP and its cognate receptor in the rheumatoid synovium and/or in cultured rheumatoid synovial endothelial cells. Endothelial cells, including apoptotic cells, as determined by TUNEL staining, were the primary site of vascular PTHrP expression in the rheumatoid synovium, a result confirmed in vitro in rheumatoid synovial microvascular endothelial cells. In contrast, the PTH/PTHrP receptor was primarily located in pericytes and smooth muscle cells within the vasculature. These results are consistent with a possible paracrine pathway for PTHrP action in the synovial microcirculation, wherein PTHrP peptides secreted by the synovial endothelium could act on surrounding PTH1R-positive pericytes and smooth muscle cells.

Arthritis, Rheumatoid↗

PubMed2002

[Insulin-like growth factor 1 (IGF-1) mRNA and IGF-1 protein. Expression in cells of the trabecular meshwork of the bovine eye].

BACKGROUND: The purpose of the study was to determine whether cultured bovine trabecular meshwork cells and trabecular tissue ex vivo express insulin-like growth factor-1 (IGF-1) mRNA and protein. METHODS: The reverse transcriptase-polymerase chain reaction (RT-PCR) was used for detection of IGF-1 mRNA. To detect the protein on the cells an IGF-1-specific immunohistochemical stain was used on trabecular meshwork cells. RESULTS: A single 240 bp RT-PCR product was obtained, the RT-PCR product was verified by sequencing and the derived sequence was homologous to the known bovine sequence. IGF-1 immunostaining was positive in the cytoplasm of trabecular meshwork cells. CONCLUSIONS: We conclude that trabecular meshwork cells produce IGF-1 mRNA and contribute to the presence of IGF-1 protein in the trabecular meshwork microenvironment as well as aqueous humor. Trabecular meshwork cells were affected by IGF-1 not only through paracrine but also through autocrine action. Whether regulations in IGF-1 production may contribute to the pathogenesis of primary open-angle glaucoma and the possibility of promoting the autocrine action of IGF-1 by trabecular meshwork cells to treat the disease is worth further investigation.

Animals↗

PubMed2002

The influence of chemical sympathectomy on pain responsivity and alpha 2-adrenergic antinociception in neuropathic animals.

We studied the effect of chemical sympathectomy by 6-hydroxydopamine (6-OHDA) on pain behavior and alpha(2)-adrenergic antinociception in rats with a spinal nerve ligation-induced neuropathy. For assessment of alpha(2)-adrenergic antinociception, the rats were treated systemically with two alpha(2)-adrenoceptor agonists, one of which only poorly (MPV-2426) and the other very well (dexmedetomidine) penetrates the blood-brain barrier. Moreover, the effect of MPV-2426 on spontaneous activity of dorsal root nerve fibers proximal to the nerve injury was determined. Systemic treatment with 6-OHDA produced a marked decrease in immunocytochemical labeling of sympathetic nerve fibers in the skin but it produced no marked change in basal pain sensitivity to mechanical stimulation either in neuropathic or sham-operated animals. Systemic administration of MPV-2426 and dexmedetomidine produced a dose-dependent tactile antiallodynic effect in neuropathic animals. Intraplantar injection of MPV-2426 had an identical antiallodynic effect independent of whether it was injected into the neuropathic or contralateral hindpaw. In a test of mechanical nociception and hyperalgesia, dexmedetomidine markedly attenuated pain responses in all experimental groups, whereas MPV-2426 had a weak but significant pain attenuating effect only in neuropathic animals. In the tail flick test, both alpha(2)-adrenoceptor agonists had a significant antinociceptive effect. The pain attenuating effect of MPV-2426 was enhanced by pretreatment with 6-OHDA, except in a test of tactile allodynia. MPV-2426-induced modulation of spontaneous activity was not a general property of dorsal root fibers proximal to the injury. The results indicate that a chemical destruction of sympathetic postganglionic nerve fibers innervating the skin does not markedly influence cutaneous pain sensitivity nor is it critical for the alpha(2)-adrenoceptor agonist-induced attenuation of pain behavior in neuropathic or non-neuropathic animals. Chemical sympathectomy, independent of neuropathy, enhanced the pain attenuating effect by MPV-2426, probably due to a peripheral action, whereas in non-sympathectomized control and neuropathic animals peripheral mechanisms have only a minor, if any, role in the alpha(2)-adrenoceptor agonist-induced antinociception.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2002

Stability and activity of specific antibodies against Streptococcus mutans and Streptococcus sobrinus in bovine milk fermented with Lactobacillus rhamnosus strain GG or treated at ultra-high temperature.

Passive local immunization against dental caries is a promising approach to its prevention, as clinical evidence of active oral or nasal immunization is still limited and controversial. By means of systemic immunization of pregnant cows with a multivalent vaccine, high titres of IgG antibodies against human cariogenic bacteria, Streptococcus mutans and Streptococcus sobrinus, were produced in bovine colostrum. The purified immune product (IP) of this preparation has a number of anticariogenic properties, such as inhibition of streptococcal adherence to saliva-coated hydroxyapatite and inhibition of glucosyltransferase enzymes. This study investigated whether IP antibodies remained active and functional when added to ultra-high temperature (UHT)-treated milk or to Lactobacillus rhamnosus GG (LGG)-fermented milk stored for an extended time. LGG was chosen because of its widely known health benefits in humans and animals. A commercial UHT toddler's milk was supplemented with IP and stored for 2 months at 5, 21 and 30 degrees C. The antistreptococcal titres in UHT milk did not decline at any temperature during storage, and UHT-IP inhibited the adherence of S. mutans for up to 2 months. This was not the case with UHT toddler's milk without IgG antibodies. Milk was fermented with live LGG cells in the presence or absence of 5% IP. The antistreptococcal titres declined to about 30% of the original titres after storage. Fresh milk alone slightly enhanced streptococcal adhesion but fresh milk with IP inhibited the adherence of S. mutans by over 50%. LGG-positive fermented milk without antibodies also inhibited (P < 0.05) the adhesion by about 40%. In both LGG-fermented and UHT immune milk, the activity of antibodies against cariogenic streptococci was maintained during the expected shelf-life of these products. From the anticariogenic point of view it may be beneficial to add bovine-specific antibodies against mutans streptococci to probiotic LGG-containing milk products.

Animals↗

PubMed2002

Production of duck-chicken chimeras by transferring early blastodermal cells.

Duck blastodermal cells isolated from Stage X embryos of Maya ducks were injected into subgerminal cavity of recipient Stage X chicken embryos treated with gamma-irradiation or untreated. Eleven somatic chimeras were obtained based on plumage color and were raised to sexual maturity. To test for germline chimerism, progeny tests were performed by mating the chimeras with Maya ducks. A total of 622 eggs was collected and incubated. Fertility rate and hatchability were 2.9% (18/622) and 1.0% (6/622), respectively. The six duck hatchlings were from Chimera 9801 and were considered to be derived from the germ cells developed from the donor Maya blastodermal cells, indicating that Chimera 9801 is a germline chimera.

Animals↗

PubMed2001

[Implantation of skeletal muscle stem cells in inhibition of fibroatrophy of ischemic myocardium: an experimental study].

OBJECTIVE: To investigate the effect of stem cells derived from autogenous skeletal muscle, namely satellite cells, and implanted into ischemic myocardium on inhibition of myocardium fibroatrophy. METHODS: The left anterodecendant arteries (LAD) of 12 adult dogs were ligated so as to establish animal model of acute myocardiac infarction. Satellite cells isolated from the greatest gluteal muscle of dogs were labeled with 4' 6-dimidino-2-phenylindone (DAPI), and then infused into the ventricular myocardium of the isogenic dogs through LAD. Specimens of ischemic myocardium were taken 2, 4, and 8 weeks after myoblast implantation. Histologic sections are examined under common light microscope and fluorescent microscope. Twelve dogs were used as controls. RESULTS: In the ischemic myocardium where satellite cells had been implanted, fibroaastrophy was efeectively inhibited. The implanted satellite cells had differentiated into fully developed striated muscle cells. Vitreous degeneration and disorder of basic structure could be observed in the ischemic myocardium in the control group. CONCLUSION: The satellite cells from autologous skeletal muscle differentiate into cardiac muscle cell-like cells in the ischemic area and inhibit fibroatrophy of the ischemic myocardium after implantation, thus bringing a hope of a new cure for myocardial damage.

Animals↗

PubMed2001

Peripheral effects of morphine in neuropathic rats: role of sympathetic postganglionic nerve fibers.

We studied the contribution of peripheral opioid receptors to the morphine-induced antinociception in rats with a spinal nerve ligation-induced neuropathy. Intraplantar (i.pl.) injection of morphine produced a stronger suppression of nociceptive reflex responses of the neuropathic limb following ipsilateral, than contralateral, administration, whereas the morphine-induced effect on the control limb was independent of the injection side. Antinociception induced by systemically administered morphine was significantly attenuated by i.pl. injection of a peripherally acting opioid receptor antagonist in neuropathic but not in sham-operated rats. Following chemical sympathectomy with 6-hydroxydopamine, antinociception was achieved at a lower dose ipsilaterally, than contralaterally, following i.pl. administration of morphine, and the morphine-induced antinociception was attenuated by a peripherally acting opioid receptor antagonist. These results indicate that peripheral opioid receptors may contribute to the morphine-induced antinociception in the spinal nerve ligation-induced model of neuropathy. Sympathectomy of the neuropathic limb may underlie, at least partly, the increased peripheral efficacy of morphine in neuropathy.

Analgesics, Opioid↗

PubMed2001

Parathyroid hormone-related protein (PTHrP) induction in reactive astrocytes following brain injury: a possible mediator of CNS inflammation.

PTHrP, a peptide induced in parenchymal organs during endotoxemia and in the synovium in rheumatoid arthritis, has recently been shown to be expressed in immature or transformed human astrocytes, but not in normal cells. This finding has led us to postulate that PTHrP might also be induced in reactive astrocytes in inflamed brain and, thus, act as a mediator of CNS inflammation. To test this hypothesis, PTHrP expression was examined following cortical stab wound injury in rats, a classical model of reactive gliosis. To determine whether PTHrP was induced in glia by TNF-alpha, a known mediator of inflammation in brain and of PTHrP induction in peripheral tissues, and to determine whether PTHrP, in turn, mediated inflammatory changes in glia, in vitro studies with rat astrocytes and glial-enriched mixed brain cells were also undertaken. Consistent with previous reports of PTHrP expression in normal brain, neurons were the primary site of immunoreactive PTHrP expression in the injured cortex 1 day after stab wound injury. Over the subsequent 3 days, specific immunostaining for PTHrP and for GFAP, a marker of reactive astrocytes, appeared in reactive astrocytes at the wound edge and in perivascular astrocytes, reaching a maximum level of expression at the last time point examined (day 4). TNF-alpha induced PTHrP expression in astrocyte and glial-enriched brain cells in vitro, suggesting that this pro-inflammatory peptide was a possible mediator of PTHrP expression in CNS inflammation. PTHrP(1-34) acted in an additive fashion with TNF-alpha to induced astrocyte expression of IL-6, a cytokine with demonstrated neuroprotective effects. Astrocyte proliferation was inhibited by PTHrP(1-34) and PTHrP(1-141), acting via a PTH/PTHrP receptor cAMP signaling pathway. These studies suggest that PTHrP, analogous to its regulatory functions in other non-CNS models of inflammation, may be an important mediator of the inflammatory response in brain.

Animals↗