Hypoxia Differentially Regulates Arterial and Venous Smooth Muscle Cell Migration.

Objective: Intimal hyperplasia (IH) is a clinical concern leading to failure of up to 50% of vein grafts and 10% of arterial grafts after 10 years with no known current treatment. Recent studies have shown that hypoxia differentially regulates proliferation of vein derived smooth muscle cells (V-SMC) compared to artery derived smooth muscle cells (A-SMC). The objective of this study is to evaluate the effect of hypoxia on cellular migration and the mechanisms underlying the differential effects of hypoxia on A-SMC and V-SMC migration.

Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR-dependent manner.

Opiates are among the most prescribed drugs for pain management. However, morphine use or abuse results in significant gut bacterial translocation and predisposes patients to serious infections with gut origin. The mechanism underlying this defect is still unknown.

Morphine modulation of toll-like receptors in microglial cells potentiates neuropathogenesis in a HIV-1 model of coinfection with pneumococcal pneumoniae.

Chronic drug users account for a third of all cases of AIDS in the United States and the progression to AIDS dementia is accelerated in opiate drug abusers. Clinically, microglial activation better correlates with HIV-associated neurocognitive disorders (HAND) than productive HIV-1 infection in the CNS. Moreover, pneumococcal pneumonia is the most common opportunistic infection in individuals with HAND.

Hypoxia differentially regulates arterial and venous smooth muscle cell proliferation via PDGFR-β and VEGFR-2 expression.

Despite intensive research studies, theories have yet to focus on the contribution of hypoxia to patency differences observed clinically between arterial vs. venous grafts. This study investigates the differential hypoxic response of smooth muscle cells (SMC) to hypoxia-derived endothelial cell (EC) growth factors.

Opioid drug abuse and modulation of immune function: consequences in the susceptibility to opportunistic infections.

Infection rate among intravenous drug users (IDU) is higher than the general public, and is the major cause of morbidity and hospitalization in the IDU population. Epidemiologic studies provide data on increased prevalence of opportunistic bacterial infections such as TB and pneumonia, and viral infections such as HIV-1 and hepatitis in the IDU population. An important component in the intravenous drug abuse population and in patients receiving medically indicated chronic opioid treatment is opioid withdrawal.

Morphine withdrawal stress modulates lipopolysaccharide-induced interleukin 12 p40 (IL-12p40) expression by activating extracellular signal-regulated kinase 1/2, which is further potentiated by glucocorticoids.

Withdrawal stress is a common occurrence in opioid users, yet very few studies have examined the effects of morphine withdrawal (MW) on immune functioning or the role of glucocorticoids in MW-induced immunomodulation. This study investigated for the first time the role of glucocorticoids in MW modulation of LPS-induced IL-12p40, a key cytokine playing a pivotal role in immunoprotection. Using WT and μ-opioid receptor knock-out mice, we show that MW in vivo significantly attenuated LPS-induced IL-12p40 mRNA and protein expression.

Morphine inhibits murine dendritic cell IL-23 production by modulating Toll-like receptor 2 and Nod2 signaling.

IL-23, produced by dendritic cells (DCs) and macrophages, plays a critical role in innate immunity against bacterial infection. Our previous studies show that morphine disrupts the IL-23/IL-17 mediated pulmonary mucosal host defense and increases susceptibility to Streptococcus pneumoniae lung infection. To determine the mechanism by which morphine modulates IL-23 production, mouse bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) were treated with morphine, and infected with S.

Chronic morphine treatment inhibits LPS-induced angiogenesis: implications in wound healing.

Delayed wound healing is a chronic problem in opioid drug abusers. We investigated the role chronic morphine plays on later stages of wound healing events using an angiogenesis model. Our results show that morphine treatment resulted in a significant decrease in inflammation induced angiogenesis.

Chronic morphine administration delays wound healing by inhibiting immune cell recruitment to the wound site.

Patients prescribed morphine for the management of chronic pain, and chronic heroin abusers, often present with complications such as increased susceptibility to opportunistic infections and inadequate healing of wounds. We investigated the effect of morphine on wound-healing events in the presence of an infection in an in vivo murine model that mimics the clinical manifestations seen in opioid user and abuser populations. We show for the first time that in the presence of an inflammatory inducer, lipopolysaccharide, chronic morphine treatment results in a marked decrease in wound closure, compromised wound integrity, and increased bacterial sepsis.

Morphine disrupts interleukin-23 (IL-23)/IL-17-mediated pulmonary mucosal host defense against Streptococcus pneumoniae infection.

Streptococcus pneumoniae is a pathogen that causes serious respiratory disease and meningitis in the immunocompromised drug abuse population. However, the precise mechanisms by which drug abuse compromises the host immune defense to pulmonary S. pneumoniae infection is not fully understood.

Opiate abuse, innate immunity, and bacterial infectious diseases.

The first line of defense against invading bacteria is provided by the innate immune system. Morphine and other opiates can immediately disrupt the body's first line of defense against harmful external bacteria. Opiate, for example morphine, abuse degrades physical and physiologic barriers, and modulates phagocytic cells (macrophages, neutrophils) and, nonspecific cytotoxic T cells (gammadelta T), natural killer cells, and dendritic cells, that are functionally important for carrying out a rapid immune reaction to invading pathogens.

Morphine withdrawal inhibits IL-12 induction in a macrophage cell line through a mechanism that involves cAMP.

There are very few studies that examine the effects that morphine withdrawal has on immune functioning, and of these even fewer describe the mechanisms by which withdrawal brings about these changes. Our previous work demonstrated that morphine withdrawal contributed to Th cell differentiation by biasing cells toward the Th2 lineage. A major finding from these studies was that IL-12 was decreased following withdrawal, and it was concluded that this decrease may be a mechanism by which morphine withdrawal is mediating Th2 polarization.

Morphine induces defects in early response of alveolar macrophages to Streptococcus pneumoniae by modulating TLR9-NF-kappa B signaling.

Resident alveolar macrophages and respiratory epithelium constitutes the first line of defense against invading lung pneumococci. Results from our study showed that increased mortality and bacterial outgrowth and dissemination seen in morphine-treated mice were further exaggerated following depletion of alveolar macrophages with liposomal clodronate. Using an in vitro alveolar macrophages and lung epithelial cells infection model, we show significant release of MIP-2 from alveolar macrophages, but not from lung epithelial cells, following 4 h of exposure of cells to pneumococci infection.

Transcriptional and epigenetic regulation of interleukin-2 gene in activated T cells by morphine.

Chronic morphine inhibits interleukin-2 (IL-2) at both the transcriptional and protein synthesis levels. The molecular mechanisms by which morphine decreases IL-2 are not fully understood. The production of IL-2 is tightly regulated by several transcription factors that bind to the IL-2 promoter.

Morphine induces CD4+ T cell IL-4 expression through an adenylyl cyclase mechanism independent of the protein kinase A pathway.

Impaired host defense mechanisms after major operative procedures and trauma are recognized as important factors in the development of infectious complication. Trauma is associated with impaired cellular immunity and CD4+ T cell Th2 differentiation. We have previously implicated morphine treatment as a possible mechanism for Th2 differentiation after injury.

Morphine withdrawal contributes to Th cell differentiation by biasing cells toward the Th2 lineage.

The consequences that drug withdrawal has on immune functioning has only recently been appreciated; however, given the wide variety of use and abuse of opiate analgesics, understanding the decrements to immune function that withdrawal from these drugs causes is of crucial importance. In previous work, we have demonstrated that morphine treatment contributes to immunosuppression by polarizing Th cells toward the Th2 lineage. In the current study, it was hypothesized that morphine withdrawal would result in Th2 differentiation and subsequent immune dysfunction.

Morphine impairs host innate immune response and increases susceptibility to Streptococcus pneumoniae lung infection.

Chronic morphine use impairs host innate immune response and increases susceptibility to bacteria and virus. In this study a novel mouse model of chronic morphine treatment, followed by intranasal inoculation with Streptococcus pneumoniae, was used to investigate microbial events and host innate immune response. Our results show that chronic morphine treatment markedly delayed neutrophil recruitment and increased bacterial burden in the lung, spleen, and blood with a subsequent increase in mortality.

Chronic morphine treatment differentiates T helper cells to Th2 effector cells by modulating transcription factors GATA 3 and T-bet.

Chronic morphine treatment in animal models has been shown to alter a number of immune parameters including suppression of cellular immunity. T helper cell differentiation into Th2 effector cell may be a major contributing factor to impaired cellular immunity following chronic drug abuse. We had previously shown that chronic morphine treatment in vivo and in vitro decreases IL-2 and IFNgamma (Th1) protein levels and increases IL-4 and IL-5 (Th2) protein levels in a time-dependent manner.

Morphine inhibits VEGF expression in myocardial ischemia.

Background: Vascular endothelial growth factor (VEGF) may contribute to the resolution of myocardial ischemia by stimulating collateral circulation. Morphine analgesia after myocardial ischemia is thought to increase infarct size. We hypothesize that morphine inhibits myocardial VEGF expression by inhibiting hypoxia-induced factor 1alpha (HIF-1alpha) and the signal transduction mechanisms involving Erk-1,2 MAP kinase (p42/p44), and PI3 kinase activity (phospho-Akt).

Morphine negatively regulates interferon-gamma promoter activity in activated murine T cells through two distinct cyclic AMP-dependent pathways.

To explore the mechanism by which morphine promotes the incidence of HIV infection, we evaluated the regulatory role of morphine on the interferon-gamma (IFN-gamma) promoter in activated T cells from wild type and mu-opioid receptor knockout mice. Our results show that morphine inhibited anti-CD3/CD28-stimulated IFN-gamma promoter activity in a dose-dependent manner. Chronic morphine treatment of T cells increased intracellular cAMP.

Mu-opioid receptor mediates chronic restraint stress-induced lymphocyte apoptosis.

Psychological stress is associated with immunosuppression in both humans and animals. Although it was well established that psychological stressors stimulate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, resulting in the release of various hormones and neurotransmitters, the mechanisms underlying these phenomena are poorly understood. In this study, mu-opioid receptor knockout (MORKO) mice were used to investigate whether the mu-opioid receptor mediates the immunosuppression induced by restraint stress.

The immunosuppressive effects of chronic morphine treatment are partially dependent on corticosterone and mediated by the mu-opioid receptor.

Wild-type and mu-opioid receptor knockout (MORKO) mice were used to investigate the role of corticosterone (CORT) and the mu-opioid receptor (MOR) in chronic morphine-mediated immunosuppression. We found that although plasma CORT concentrations in CORT infusion (10 mg/kg/day) and morphine-pellet implantation (75 mg) mice were similar (400-450 ng/ml), chronic morphine treatment resulted in a significantly higher (two- to threefold) inhibition of thymic, splenic, and lymph node cellularity; inhibition of thymic-lymphocyte proliferation; inhibition of IL-2 synthesis; and activation of macrophage nitric oxide (NO) production when compared with CORT infusion. In addition, results show that the inhibition of IFN-gamma synthesis and splenic- and lymph node-lymphocyte proliferation and activation of macrophage TNF-alpha and IL-1beta synthesis occurred only with chronic morphine treatment but not with CORT infusion.