Biomedical subjects

H L Rittner

Publications and source records attributed to H L Rittner.

15 recordsLinked to original sources

PubMed2006

Interleukin-1 beta contributes to the upregulation of kappa opioid receptor mrna in dorsal root ganglia in response to peripheral inflammation.

During local painful inflammation, axonal transport of opioid receptors from dorsal root ganglia toward the periphery is increased, associated with a higher receptor density and enhanced efficacy of opioid analgesics at the injured site. To examine whether this increase is related to transcription, mRNA of the kappa opioid receptor in lumbar dorsal root ganglia was quantified by real time light cycler polymerase chain reaction. In dorsal root ganglia of naive rats, kappa opioid receptor mRNA expression was three-fold higher than previously shown for delta opioid receptor and two times lower than mu opioid receptor mRNA, respectively. After induction of unilateral paw inflammation by Freund's complete adjuvant, kappa opioid receptor mRNA was significantly upregulated with a peak at 12 h in ipsilateral dorsal root ganglia. This effect could be mimicked by intraplantar injection of the proinflammatory cytokine interleukin-1 beta. Kappa opioid receptor mRNA upregulation lasted longer in interleukin-1 beta-treated rats compared with Freund's complete adjuvant-treated rats. Furthermore, a significant increase in kappa opioid receptor positive neurons was detected by immunohistochemistry 24 h after local injection of Freund's complete adjuvant or interleukin-1 beta. In Freund's complete adjuvant-induced inflammation, kappa opioid receptor upregulation was blocked by treatment with interleukin-1 receptor antagonist without changing the leukocyte infiltration in the paw. In conclusion, kappa opioid receptor mRNA and protein in dorsal root ganglia are upregulated in response to peripheral inflammation. This effect can be mimicked by a single local injection of interleukin-1 beta, and Freund's complete adjuvant-induced upregulation in kappa opioid receptor mRNA and protein can be prevented by treatment with interleukin-1 receptor antagonist. These data suggest that the peripheral production of the proinflammatory cytokine interleukin-1 beta is a specific inducer of kappa opioid receptor expression in the dorsal root ganglia.

Animals↗

PubMed2005

Leukocytes in the regulation of pain and analgesia.

When tissue is destroyed or invaded by leukocytes in inflammation, numerous mediators are delivered by the circulation and/or liberated from resident and immigrated cells at the site. Proalgesic mediators include proinflammatory cytokines, chemokines, protons, nerve growth factor, and prostaglandins, which are produced by invading leukocytes or by resident cells. Less well known is that analgesic mediators, which counteract pain, are also produced in inflamed tissues. These include anti-inflammatory cytokines and opioid peptides. Interactions between leukocyte-derived opioid peptides and opioid receptors can lead to potent, clinically relevant inhibition of pain (analgesia). Opioid receptors are present on peripheral endings of sensory neurons. Opioid peptides are synthesized in circulating leukocytes, which migrate to inflamed tissues directed by chemokines and adhesion molecules. Under stressful conditions or in response to releasing agents (e.g., corticotropin-releasing factor, cytokines, noradrenaline), leukocytes can secrete opioids. They activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuropeptides. This review presents discoveries that led to the concepts of pain generation by mediators secreted from leukocytes and of analgesia by immune-derived opioids.

Analgesia↗

PubMed2005

[Critical reevaluation of cyclooxygenase two inhibitors in perioperative pain therapy].

A significant increase in thromboembolic events (i.e. myocardial infarction and stroke) was demonstrated in multicenter studies after several months of treatment with cyclooxygenase 2 (cox-2) inhibitors. In February 2005, the European medical agencies (EMEA) substantially increased the number of contraindications for all cox-2 inhibitors. They are now contraindicated for patients with coronary artery disease. Furthermore, 2 out of 6 cox-2 inhibitors have been withdrawn from the market. In this review, the current state of knowledge on the use of cox-2 inhibitors in perioperative pain therapy is summarized: i) they are equally as potent as other non-opioid analgesics, ii) they decrease opioid consumption, iii) a reduction in postoperative nausea and vomiting (PONV) has not been adequately demonstrated. Regarding side-effects, it can be concluded that i) the incidence of thromboembolic events is increased in patients undergoing coronary artery bypass surgery, ii) perioperative blood loss is not affected, iii) ulcer formation is not promoted, iv) the risk for acute renal failure is probably increased to the same extent as for NSAIDs and v) severe bronchospasm can be triggered in patients with asthma and chronic obstructive pulmonary disease (COPD).

Contraindications↗

PubMed2005

Involvement of cytokines, chemokines and adhesion molecules in opioid analgesia.

Tissue destruction is accompanied by an inflammatory reaction. The inflammatory reaction leads to activation of nociceptors and the sensation of pain. Several mediators are responsible for pain and hyperalgesia in inflammation including cytokines, chemokines, nerve growth factor as well as bradykinin, prostaglandins and ATP. Simulatenously however, analgesic mediators are secreted: opioid peptides, somatostatin, endocannabinoids and certain cytokines. Opioid peptides secreted from immune cells are so far the best studied peptides in peripheral inflammatory pain control. This system is hampered for example by anti-adhesion molecule treatment. Novel immunosuppressive drugs for treatment of autoimmune disease targetting cytokines, chemokines or adhesion molecules should therefore be evaluated for potential harmful effects on pain.

Analgesia↗

PubMed2004

[Non-opioid analgesics for perioperative pain therapy. Risks and rational basis for use].

Non-opioid analgesics play a central role in the management of postoperative pain. In this review, the pharmacology, the analgesic efficacy and the side-effects of non-opioid analgesics are summarized. First, the pharmacology of diclofenac, acetyl salicylic acid, dipyrone, acetaminophen and the COX-2 inhibitors is described. Second, the analgesic efficacy of non-opioid analgesics is analyzed for moderate pain (e.g. ambulatory surgery) and for moderate to severe pain (e.g. abdominal surgery-in combination with opioids). There is limited evidence for an additive analgesic effect of two non-opioid analgesics. Third, the major side-effects of non-opioid analgesics are discussed in relation to the pathophysiology, the frequency and the clinical relevance of these effects. In particular, side-effects on the gastrointestinal tract (ulcus formation), on coagulation (bleeding and thrombosis), on the renal (renal insufficiency), the pulmonary (bronchospasm) and the hematopoetic systems (agranulocytosis) are described. Recommendations for the clinical use of non-opioid analgesics for perioperative pain therapy are given.

Acute Kidney Injury↗

PubMed2004

Detection of germ-cell-tumor-specific gene products in peripheral blood by immunomagnetic tumor cell enrichment followed by RT-PCR.

Therapeutic procedures in patients with testicular germ cell tumors (GCT) are determined by the histopathology of the primary tumor and the tumor extension. The aim of our study was to determine whether conventional staging could be supplemented by combining enrichment of disseminated testicular GCT cells from peripheral blood with subsequent detection of germ-cell-specific gene products. Blood samples from 46 patients with GCT of different clinical stages (CS) were examined by RT-PCR before therapy and >/=8 weeks thereafter for alpha-fetoprotein, beta-human chorionic gonadotropin and germ-cell-specific alkaline phosphatase mRNA. In addition, we performed titration experiments to evaluate whether the sensitivity can be improved by previous immunomagnetic tumor cell enrichment with anti-epithelial HEA-125 microbeads. No positive results were found in controls (n=15; specificity 100%). The overall ratio of positive PCR results in the group of patients with GCTs was 28.26%. The ratio was 35.7% for CS >IIb (n=5/14 patients), 20.0% for CS IIa-b (n=4/20) and 33.3% for CS I (n=4/12). FACS analysis in titration experiments with GCT cell lines showed that previous immunomagnetic tumor cell enrichment achieved a significant increase ranging up to 185.6 times the initial ratio and thus improved the measuring conditions for detection of tumor-specific transcripts. The sole qualitative RT-PCR of tumor-specific gene products in peripheral blood is not sensitive enough to improve staging in GCT patients. Immunomagnetic enrichment of GCT cells in peripheral blood seems a promising approach for increasing the sensitivity of RT-PCR.

Calcium-Binding Proteins↗

PubMed2002

[Pain and the immune system: friend or foe?].

When tissue is destroyed, pain arises. Tissue destruction as well as wound healing are associated with an inflammatory reaction. This leads to activation of nociceptors ("pain receptors") which can cross-communicate with the inflammatory infiltrate. The following review will concentrate on pain-exaggerating (hyperalgesic) and pain-ameliorating (analgesic) mediators which arise from immune cells or the circulation during the inflammation. In the early stages of inflammation endogenous hyperalgesic mediators are produced, including the proinflammatory cytokines IL-1, IL-6 and TNF-alpha, nerve growth factor as well as bradykinin and prostaglandins. Simultaneously, analgesic mechanisms are activated. Opioid peptides such as endorphins, enkephalins and dynorphins are produced by immune cells and can be released locally in the inflamed tissue on stimulation with IL-1 or corticotropin releasing factor. Analgesia is elicited by binding of the opioid peptides to receptors on peripheral sensory neurons. During the course of an inflammatory process, peripheral opioid-mediated analgesia increases. In parallel, antiinflammatory cytokines such as IL-4, IL-10, IL-13 and IL-1ra are produced and reduce hyperalgesic effects of the proinflammatory cytokines initially produced. Inflammatory pain, therefore, is the result of an interplay between hyperalgesic and analgesic mediators. Drugs such as immunosuppressants influencing this interplay may also impair endogenous hyperalgesic and analgesic mechanisms.

Humans↗

PubMed2001

Opioid peptide-expressing leukocytes: identification, recruitment, and simultaneously increasing inhibition of inflammatory pain.

BACKGROUND: Inflammatory pain can be effectively controlled by an interaction of opioid receptors on peripheral sensory nerve terminals with opioid peptides released from immune cells upon stressful stimulation. To define the source of opioid peptide production, we sought to identify and quantify populations of opioid-containing cells during the course of Freund's complete adjuvant-induced hind paw inflammation in the rat. In parallel, we examined the development of stress-induced local analgesia in the paw. METHODS: At 2, 6, and 96 h after Freund's complete adjuvant inoculation, cells were characterized by flow cytometry using a monoclonal pan-opioid antibody (3E7) and antibodies against cell surface antigens and by immunohistochemistry using a polyclonal antibody to beta-endorphin. After magnetic cell sorting, the beta-endorphin content was quantified by radioimmunoassay. Pain responses before and after cold water swim stress were evaluated by paw pressure thresholds. RESULTS: In early inflammation, 66% of opioid peptide-producing (3E7+) leukocytes were HIS48+ granulocytes. In contrast, at later stages (96 h), the majority of 3E7+ immune cells were ED1+ monocytes or macrophages (73%). During the 4 days after Freund's complete adjuvant inoculation, the number of 3E7+ cells increased 5.6-fold (P < 0.001, Kruskal-Wallis test) and the beta-endorphin content in the paw multiplied 3.9-fold (P < 0.05, Kruskal-Wallis test). In parallel, cold water swim stress-induced analgesia increased by 160% (P < 0.01, analysis of variance). CONCLUSIONS: The degree of endogenous pain inhibition is proportional to the number of opioid peptide-producing cells, and distinct leukocyte lineages contribute to this function at different stages of inflammation. These mechanisms may be important for understanding pain in immunosuppressed states such as cancer, diabetes, or AIDS and for the design of novel therapeutic strategies in inflammatory diseases.

Analgesia↗

PubMed2000

Anti-psoriatic drug anthralin activates JNK via lipid peroxidation: mononuclear cells are more sensitive than keratinocytes.

Anthralin is a widely used, topical therapy for psoriasis. Anti-proliferative and anti-inflammatory properties of anthralin have been identified. Little is known, however, about differential sensitivities of targeted cell types and specific mechanisms of signaling pathway activation. We demonstrate that anthralin exerts potent effects on keratinocytes and mononuclear cells through strong induction of lipid peroxidation and JNK activation, a stress-induced signal transduction pathway. Lipid peroxidation was observed rapidly and half-maximal levels of lipid peroxidation were reached at a 10-fold lower concentration of anthralin for peripheral blood mononuclear cells vs normal keratinocytes. JNK activation was detected in peripheral blood mononuclear cells at a 40-fold lower anthralin dose compared with keratinocytes. For both cell types, selected inhibitors of lipid peroxidation prevented JNK activation. This study demonstrates that mononuclear leukocytes are markedly more sensitive than keratinocytes to anthralin-induced lipid peroxidation and JNK activation. We identify anthralin as a novel and potent inducer of JNK activation and demonstrate that this process is mediated, at least in part, by lipid peroxidation which is among the earliest and most proximate, membrane-related responses to anthralin yet described.

Administration, Topical↗

PubMed1999

Tissue-destructive macrophages in giant cell arteritis.

Giant cell arteritis (GCA) is an inflammatory vasculopathy in which T cells and macrophages infiltrate the wall of medium and large arteries. Clinical consequences such as blindness and stroke are related to arterial occlusion. Formation of aortic aneurysms may result from necrosis of smooth muscle cells and fragmentation of elastic membranes. The molecular mechanisms of arterial wall injury in GCA are not understood. To identify mechanisms of arterial damage, gene expression in inflamed and unaffected temporal artery specimens was compared by differential display polymerase chain reaction. Genes differentially expressed in arterial lesions included 3 products encoded by the mitochondrial genome. Immunohistochemistry with antibodies specific for a 65-kDa mitochondrial antigen revealed that increased expression of mitochondrial products was characteristic of multinucleated giant cells and of CD68+ macrophages that cluster in the media and at the media-intima junction. 4-Hydroxy-2-nonenal adducts, products of lipid peroxidation, were detected on smooth muscle cells and on tissue infiltrating cells, in close proximity to multinucleated giant cells and CD68+ macrophages. Also, giant cells and macrophages with overexpression of mitochondrial products were able to synthesize metalloproteinase-2. Our data suggest that in the vascular lesions characteristic for GCA, a subset of macrophages has the potential to support several pathways of arterial injury, including the release of reactive oxygen species and the production of metalloproteinase-2. This macrophage subset is topographically defined and is also identified by overexpression of mitochondrial genes. Because these macrophages have a high potential to promote several mechanisms of arterial wall damage, they should be therapeutically targeted to prevent blood vessel destruction.

Antigens, CD↗

PubMed1999

Aldose reductase functions as a detoxification system for lipid peroxidation products in vasculitis.

Giant cell arteritis (GCA) is a systemic vasculitis preferentially affecting large and medium-sized arteries. Inflammatory infiltrates in the arterial wall induce luminal occlusion with subsequent ischemia and degradation of the elastic membranes, allowing aneurysm formation. To identify pathways relevant to the disease process, differential display-PCR was used. The enzyme aldose reductase (AR), which is implicated in the regulation of tissue osmolarity, was found to be upregulated in the arteritic lesions. Upregulated AR expression was limited to areas of tissue destruction in inflamed arteries, where it was detected in T cells, macrophages, and smooth muscle cells. The production of AR was highly correlated with the presence of 4-hydroxynonenal (HNE), a toxic aldehyde and downstream product of lipid peroxidation. In vitro exposure of mononuclear cells to HNE was sufficient to induce AR production. The in vivo relationship of AR and HNE was explored by treating human GCA temporal artery-severe combined immunodeficiency (SCID) mouse chimeras with the AR inhibitors Sorbinil and Zopolrestat. Inhibition of AR increased HNE adducts twofold and the number of apoptotic cells in the arterial wall threefold. These data demonstrate that AR has a tissue-protective function by preventing damage from lipid peroxidation. We propose that AR is an oxidative defense mechanism able to neutralize the toxic effects of lipid peroxidation and has a role in limiting the arterial wall injury mediated by reactive oxygen species.

Aldehyde Reductase↗

PubMed1997

Glucocorticoid-mediated repression of cytokine gene transcription in human arteritis-SCID chimeras.

Giant cell arteritis (GCA) is a vasculitic syndrome that preferentially affects medium and large-sized arteries. Glucocorticoid therapy resolves clinical symptoms within hours to days, but therapy has to be continued over several years to prevent disease relapses. It is not known whether and how glucocorticoids affect the function of the inflammatory infiltrate or why the disease persists subclinically despite chronic treatment. GCA is self-sustained in temporal arteries engrafted into SCID mice, providing a model in which the mechanisms of action and limitations of glucocorticoid therapy can be examined in vivo. Administration of dexamethasone to temporal artery-SCID chimeras for 1 wk induced a partial suppression of T cell and macrophage function as indicated by the reduced tissue concentrations of IL-2, IL-1beta, and IL-6 mRNA, and by the diminished expression of inducible NO synthase. In contrast, synthesis of IFN-gamma mRNA was only slightly decreased, and expression of TGF-beta1 was unaffected. These findings correlated with activation of the IkappaBalpha gene and blockade of the nuclear translocation of NFkappaB in the xenotransplanted tissue. Dose-response experiments suggested that steroid doses currently used in clinical medicine are suboptimal in repressing NFkappaB-mediated cytokine production in the inflammatory lesions. Chronic steroid therapy was able to deplete the T cell products IL-2 and IFN-gamma, whereas the activation of tissue-infiltrating macrophages was only partially affected. IL-1beta transcription was abrogated; in contrast, TGF-beta1 mRNA synthesis was steroid resistant. The persistence of TGF-beta1-transcribing macrophages, despite paralysis of T cell function, may provide an explanation for the chronicity of the disease, and may identify a novel therapeutic target in this inflammatory vasculopathy.

Animals↗

PubMed1997

Developmental patterns of serum 3 alpha-androstanediol glucuronide.

3 alpha-androstanediol glucuronide (3 alpha diolG) is a marker of peripheral tissue androgen metabolism. There are no previous data regarding complete paediatric reference ranges for 3 alpha diolG. In order to obtain reference values for 3 alpha diolG we have measured serum levels of 3 alpha diolG in 283 healthy children and adolescents, 146 boys and 137 girls, age 1 month to 20 years and 28 adults. A non-extraction, solid phase radioimmunoassay employing a polyclonal antiserum that is specific for 3 alpha diolG was used to measure serum 3 alpha diolG levels (intra assay variation 5.1-10.1%, inter assay variation 2.7-9.0%). There was a strong sex and age dependence (r = 0.8; p < 0.0001) of 3 alpha diolG levels throughout childhood and adolescence with males showing significantly higher levels of the androgen than females (p < 0.05). 3 alpha diolG serum levels (nmol/l +/- SD) correlated significantly with pubertal stage (p < 0.01). Interestingly, in 35 children with CAH serum 3 alpha diolG levels correlated well with clinical and metabolic status, i.e. 17OHP serum levels. In summary, we have established percentile curves for 3 alpha diolG levels in healthy children and adolescents. We hypothesize that on the basis of our reference values the single measurement of serum 3 alpha diolG could serve as a means to determine androgen status in children with disorders of puberty and sexual development.

17-alpha-Hydroxyprogesterone↗

PubMed1997

Developmental patterns of serum 3 alpha-androstanediol glucuronide.

Adolescent↗

PubMed1997

Multiple mechanisms support oligoclonal T cell expansion in rheumatoid synovitis.

BACKGROUND: The synovial T cell infiltrate in rheumatoid arthritis (RA) is diverse but contains clonally expanded CD4+ populations. Recent reports have emphasized that RA patients have a tendency to develop CD4+ T cell oligoclonality which also manifests in the peripheral blood. Clonal dominance in the tissue may thus result from antigen specific stimulation in the synovial membrane or may reflect the infiltration of expanded clonotypes present throughout the lymphoid system. We have explored to what extent clonal populations amongst tissue CD4+ T cells display joint specificity as defined by their restriction to the joint, their persistence over time, and their expression of markers indicative for local activation. MATERIALS AND METHODS: Matched samples of peripheral blood and synovial fluid or synovial tissue were collected from 14 patients with active RA and CD4+ IL-2R+ and CD4+ IL-2R- T cells from both compartments were purified. Clonal populations of CD4+ T cells were detected by RT-PCR amplification of T cell receptor (TCR) transcripts with BV and BJ specific primers followed by size fractionation and direct sequencing of dominant size classes of TCR transcripts. RESULTS: Clonal CD4+ T cells were detected in the synovial fluid and synovial tissue of all patients. All patients carried synovial clonotypes that were undetectable in the blood but were present in independent joints or at several non-adjacent areas of the same joint. These joint restricted CD4+ clonotypes were generally small in size, were preferentially found in the IL-2R+ subpopulation, and persisted over time. A second type of clonogenic T cells in the synovial infiltrate had an unrestricted tissue distribution and was present at similar frequencies amongst activated and nonactivated T cells in the blood and affected joints. Ubiquitous clonotypes isolated from two different patients expressed sequence homologies of the TCR beta chain. CONCLUSIONS: Two types of expanded CD4+ clonotypes contribute to the T cell infiltrate in rheumatoid synovitis. Differences in the distribution pattern and in molecular features suggest that distinct mechanisms are supporting the clonal outgrowth of these two groups of clonotypes. Clonally expanded T cells restricted to the joint but present in several independent joints appear to respond to locally residing antigens. Clonogenic cells with an unrestricted distribution pattern and widespread activation in the blood and tissue may react to a different class of antigens which appear to be shared by multiple patients. T cell recognition in RA may be involved at several different levels and may be related to more than one pathomechanism.

Adult↗