Treatment Of Chronic Inflammatory Diseases Research Articles

Clinical and immunologic parameters during thalidomide treatment of lupus erythematosus.

Thalidomide is used as an experimental drug for the treatment of chronic inflammatory diseases with an autoimmune or infectious background. The pharmacologic action involves the downregulation of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and inhibition of basic fibroblast growth factor (bFGF)-induced angiogenesis; however, not much is known about thalidomide's effect on immunologic parameters in lupus erythematosus (LE). Method This is an open study of a group of five consecutive systemic lupus erythematosus (SLE) patients treated with thalidomide (100 mg/day) and five consecutive cutaneous LE patients not responsive to conventional therapy. The clinical and immunologic parameters (C-reactive protein, immunoglobulin, and complement serum levels, lymphocyte counts) were investigated during thalidomide treatment for up to 2 years in both patient groups. An increase in the absolute peripheral lymphocyte count was observed beginning after 2 weeks of systemic thalidomide treatment in nine out of 10 LE patients, and remained stable throughout thalidomide treatment. Elevated serum levels of C-reactive protein and titers of autoantibodies to double-stranded (ds) DNA decreased in SLE patients. No significant changes were detected in the serum levels of the complement components C3 and C4 and immunoglobulins in all LE patients. Regression of inflammatory skin lesions and regrowth of hair were recorded. As a side-effect, polyneuropathy was observed in four out of 10 patients, with the earliest onset at 3 weeks of thalidomide treatment. Thalidomide is a potent anti-inflammatory drug in patients with SLE and cutaneous LE, possibly interacting with the recruitment of lymphocytes. It leads to the regrowth of hair in LE-related alopecia and effluvium. Early symptoms of polyneuropathy should be registered and the drug should be withdrawn. Thalidomide should be restricted to patients who show no response to standard therapeutic regimens and should only be used under strict precautions with regard to its known teratogenic risk.

COX-1, COX-2, and COX-3 and the future treatment of chronic inflammatory disease

A new generation of non-steroidal anti-inflammatory drugs has been described that selectively targets the inducible isoform of cyclo-oxygenase, cyclo-oxygenase 2 (COX-2). This isoform is expressed at sites of inflammation, which has led to the speculation that its inhibition could provide all the benefits of current nonsteroidal anti-inflammatory drugs, but without their major side-effects on the gastrointestinal system (which are due to inhibition of COX-1). We have shown that COX-2 (identified by use of specific antibodies) is induced during the resolution of an inflammatory response, inhibition of COX-2 resulting in persistence of the inflammation due to the prevention of the synthesis of a range of anti-inflammatory prostanoids. We propose that there is a third isoform of this enzyme family, COX-3, a proposal that will have implication for the prescription of both existing and new generation anti-inflammatory drugs, and might represent a new therapeutic target.

Arachidonic acid release induced by LPS in microglial cells

Cytosolic phospholipase A2 (cPLA2) plays a pivotal role in inflammation by catalyzing the release of arachidonic acid, a substrate for lipoxygenase and cyclooxygenase enzymes, from membrane phospholipids. In the present study we examined the role of cPLA2 in inflammatory responses through the use of a specific inhibitor of the enzyme, cPLA2, arachidonyl trifluoromethyl ketone (AACOCF3). Interestingly, we observed that AACOCF3 is an inhibitor of chronic but not acute inflammatory responses. Specifically, AACOCF3 inhibited phorbol 12-myristate 13-acetate (PMA)-induced chronic ear edema in mice. Additionally, oral treatment of ovalbumin-sensitized/ovalbumin-challenged BALB/c mice with 20 mg/kg AACOCF3 prevented the development of airway hyper-responsiveness in a model of asthma. Furthermore, AACOCF3 decreased cellular recruitment in the airway lumen and airway inflammation after the ovalbumin challenge. Taken together, these results suggest that a potent and specific chemical inhibitor of cPLA2 may be useful for the treatment of chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and asthma.

Discovery of novel non-peptide CCR1 receptor antagonists.

Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.

New insights into the roles of ReL/NF- κB transcription factors in immune function, hemopoiesis and human disease

In mammals, Rel/NF- κB proteins are a small family of transcription factors which serve as pivotal regulators of immune, inflammatory and acute phase responses. Pathways leading to the activation of Rel/NF- κB have recently been dissected in some detail and shown to converge on a unique high molecular weight cytoplasmic complex that includes several kinases and regulatory molecules. Moreover, gene targeting experiments have identified novel roles for Rel/NF- κB proteins in the development and maturation of hemopoietic precursors as well as in the function of mature cells in the immune system. These include regulating the cell cycle, controlling cell survival and providing a link between the innate and adaptive immune systems. Since the dysregulation of Rel/NF- κB function is associated with various pathologies including inflammatory and neoplastic disease, new insights into the role of Rel/NF- κB in human disease may provide a basis for therapeutic strategies in the treatment of chronic inflammatory diseases and certain malignancies.

Doxycycline Induces Fas/Fas Ligand-Mediated Apoptosis in Jurkat T Lymphocytes

Tetracyclines have been used in the treatment of chronic inflammatory diseases associated with local infiltration of inflammatory cells and matrix destruction as observed in rheumatoid arthritis and periodontal disease. Fas/Fas ligand (FasL)-mediated apoptosis plays an important role in maintaining T lymphocyte homeostasis and modulating immune response. The present study demonstrates that doxycycline inhibits Jurkat T lymphocyte proliferation and induces apoptosis. The phytohemagglutinin (PHA)-activated Jurkat cells are more susceptible to doxycycline-induced apoptosis. Furthermore, doxycycline-induced apoptosis is associated with increased Fas/FasL expression in Jurkat cells. The increase of apoptosis in Jurkat cells treated with doxycycline is consistent with the increase of FasL expression. These results suggest that doxycycline may downregulate the inflammatory process in certain diseases by eliminating activated T lymphocytes through Fas/FasL-mediated apoptosis.

Selective Regulation of Cytokine Induction by Adenoviral Gene Transfer of IκBα into Human Macrophages: Lipopolysaccharide-Induced, But Not Zymosan-Induced, Proinflammatory Cytokines Are Inhibited, But IL-10 Is Nuclear Factor-κB Independent

AbstractMacrophages are the major cytokine producers in chronic inflammatory diseases, but the biochemical pathways regulating cytokine production are poorly understood. This is because genetic tools to dissect signaling pathways cannot be used in macrophages because of difficulties in transfection. We have developed an adenoviral technique to achieve high efficiency gene delivery into macrophages and recently showed that spontaneous TNF-α production in rheumatoid arthritis joint cells, chiefly from macrophages, is 75% blocked by adenoviral transfer of IκBα. In this report we use the same adenovirus to investigate whether the production of a number of proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, and IL-8) from human macrophages depends on NF-κB. While the cytokine response to certain inducers, such as LPS, PMA, and UV light, is blocked by overexpression of IκBα, the response to zymosan is not. In contrast, anti-inflammatory mediators (IL-10 and IL-1 receptor antagonist) induced by LPS are only marginally inhibited by IκBα excess. These studies demonstrate several new points about macrophage cytokine production. First, there is heterogeneity of mechanisms regulating both the proinflammatory and anti-inflammatory cytokines within populations of a single cell type. In addition, the results confirm the utility of the adenoviral technique for functional analysis of cytokine induction. The results also confirm that there are autocrine and paracrine interactions regulating cytokine synthesis within a single cell type. The selectivity of NF-κB blockade for proinflammatory but not anti-inflammatory mediators indicates that in macrophages, NF-κB may be a good target for the treatment of chronic inflammatory diseases.

Identification and Characterization of Small Molecule Functional Antagonists of the CCR1 Chemokine Receptor

The CC chemokines macrophage inflammatory protein-1alpha (MIP-1alpha) and RANTES (regulated on activation normal T cell expressed) have been implicated in rheumatoid arthritis and multiple sclerosis. Since their effects are mediated through the CCR1 chemokine receptor, we set up a small molecule CCR1 antagonist program to search for inhibitors. Through high capacity screening we discovered a number of 4-hydroxypiperidine compounds with CCR1 antagonist activity and report their synthesis and in vitro pharmacology here. Scatchard analysis of the competition binding data revealed that the compounds had Ki values ranging from 40 to 4000 nM. The pharmacological profile of the most potent member of this series, compound 1 (2-2-diphenyl-5-(4-chlorophenyl)piperidin-lyl)valeronitri te), was further evaluated. Compound 1 showed concentration-dependent inhibition of MIP-1alpha-induced extracellular acidification and Ca2+ mobilization demonstrating functional antagonism. When given alone, the compound did not elicit any responses, indicating the absence of intrinsic agonist activity. Compound 1 inhibited MIP-1alpha- and RANTES-induced migration in peripheral blood mononuclear cells in a dose-responsive manner. Selectivity testing against a panel of seven transmembrane domain receptors indicated that compound 1 is inactive on a number of receptors at concentrations up to 10 microM. This is the first description of CCR1 receptor antagonists that may be useful in the treatment of chronic inflammatory diseases involving MIP-1alpha, RANTES, and CCR1.

Neovir (kamedon), an interferon inductor in the complex treatment of chronic inflammatory diseases of the uterine appendages of the chlamydial etiology (a clinical electron microscopic investigation): Delektorsky V.V.; Malinovskay V.V.; Strizhakow A.N.; Yashkova G.N.; Kagramanova Zh.A.; Genkin D.D.; Parfenov V.V.; Galyautdinov D.Sh.; Balandin A.N.; Lebedeva T.V. RUS Antibiot Khimioter 1995 40/5 (42–47)

Neovir (kamedon), an interferon inductor in the complex treatment of chronic inflammatory diseases of the uterine appendages of the chlamydial etiology (a clinical electron microscopic investigation): Delektorsky V.V.; Malinovskay V.V.; Strizhakow A.N.; Yashkova G.N.; Kagramanova Zh.A.; Genkin D.D.; Parfenov V.V.; Galyautdinov D.Sh.; Balandin A.N.; Lebedeva T.V. RUS Antibiot Khimioter 1995 40/5 (42–47)

Distribution of cyclooxygenase isoforms in murine chronic granulomatous inflammation. Implications for future anti‐inflammatory therapy

Inhibition of the enzyme cyclooxygenase (COX) is the basis for the mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs). COX exists as a constitutive (COX-1) and a mitogen-inducible (COX-2) isoform. The relative contribution of COX-1 and COX-2 to inflammation is unknown. This study investigated COX activity and the distribution of COX-1 and COX-2 during the development of a murine air pouch model of chronic granulomatous inflammation. COX activity progressively rose and was maximal at day 14. Of the COX metabolites measured, PGE2 was the greatest > 6-keto PGF1a > TXB2 > PGF2a. By day 7, COX-2-labelled fibroblast- and macrophage-like cells were observed and their number and distribution increased with time. At all time points, endothelial cells of venules in the loose connective tissue of the dermis showed immunoreactivity for COX-2. After day 14, labelling of capillaries in the granuloma was also observed. This study is the first to show that COX-2 is the predominant COX isoform in all stages of the inflammatory response. These results suggest that selective inhibition of COX-2 may prove more beneficial, with fewer gastric and renal side-effects, than existing NSAID therapy for the treatment of chronic inflammatory diseases.

Anti-inflammatory activity of the isoquinoline alkaloid, tetrandrine, against established adjuvant arthritis in rats.

Two isoquinoline plant alkaloids, tetrandrine (1) and berbamine (2), have been evaluated for anti-inflammatory activity in an acute paw oedema assay and in adjuvant-induced arthritis in rats. 1 but not 2 suppressed the chronic inflammation in the arthritis model but neither compound was active in the acute inflammation assay. In the adjuvant-induced polyarthritis, 1 was not effective when given at the time of inoculation (Day 0), nor just before (Day 7-10) signs of arthritis were evident. However, when given on a therapeutic dose schedule (Days 10-13) or continually (Day -1 to +14) on a prophylactic schedule, signs of arthritis including weight loss due to cachexia were significantly reduced. Given orally, 1 was considerably more potent than aspirin but not gastro-irritant and may be a promising lead for the development of a safe and effective treatment of chronic inflammatory diseases.

Electron-microscopic and autoradiographic study of changes in bronchoalveolar washings in chronic inflammation of the lungs treated by helium-neon laser

The morphological manifestations of the clinical effect of laser irradiation have received little study. The role of the cell membrane structures in the formation of the response to laser irradiation, reflected in stimulation of energy metabolism and biosynthetic processes has been demonstrated experimentally [2]. The biostimulating effect of laser therapy has been related to induction of regeneration [i, 4, 13, 14]. If laser therapy is included in the combination treatment of chronic inflammatory diseases of the lungs, the structural changes arising in the air passages can be studied with the aid of bronchial biopsy [8]. However, no morphological investigations of respiratory tissues have been described in the literature.

Anti-inflammatory and immunosuppressive properties of the bis-benzylisoquinolines: In vitro comparisons of tetrandrine and berbamine

Tetrandrine and berbamine are two naturally occuring analogues with a bis-benzylisoquinoline structure. Comparative in vitro studies show that tetrandrine has significantly greater suppressive effects on adherence, locomotion and 3H-deoxyglucose uptake of neutrophils, as well as the mitogen-induced lymphocyte responses and mixed lymphocyte reactions. Also, tetrandrine displayed anti-oxidant activity while berbamine did not. By contrast, berbamine demonstrated a significantly greater capacity for inhibition of NK cell cytotoxicity. These results show that tetrandrine is superior to berbamine in most aspects of anti-inflammatory and immunosuppressive activity. Since these two alkaloids differ by only one substitution in the side chain of one of the benzene rings, these findings may provide further insight into structure — activity relationships and clues to the synthesis and development of active analogues of this promising class of drugs for the treatment of chronic inflammatory diseases.

Effect of tetrandrine on immunological responses and cardiac transplant rejection in mice.

Mice treated with the plant alkaloid tetrandrine have a reduced capacity to mount delayed-type hypersensitivity (DTH) responses. This suppressive effect on DTH was more pronounced when treatment was begun 2 days prior to immunization with sheep erythrocytes. Similar dosage regimens significantly delayed the rejection of cardiac transplants. By contrast, there was significant enhancement of antibody production. These immunomodulatory properties of tetrandrine may account for some of its potential in the treatment of chronic inflammatory diseases, where immunological mechanisms are known to play a major role in pathogenesis.

Carcinogenesis due to mustard gas exposure in man, important sign for therapy with alkylating agents

Sulphur-mustard and nitrogen-mustard are known to act as carcinogens in animal experiments. A similar effect in humans was demonstrated in 245 workers previously exposed occupationally to mustard gas and followed for over 20 years. There was a statistically significant increase in malignant tumours, especially bronchial carcinoma, bladder carcinoma and leukaemia. These findings underline the need for using alkylating agents of the mustard type exclusively in the treatment of malignant neoplasms. Immunosuppression with alkylating agents in the treatment of chronic inflammatory diseases associated with a long life expectancy is no longer justified.

Renal Amyloidosis—A Fourteen-year Follow-up

Forty-eight cases of histologically proven renal amyloidosis are presented, with clinical details and follow-up data of up to 14 years following establishment of the diagnosis. The average length of follow-up was 29 months. The diagnosis was established by fluorescence with Thioflavine T and Congo Red birefringence throughout the series, and the last seven renal biopsies were confirmed by electron microscopy. The over-all incidence of renal amyloidosis in a series of 1,500 renal biopsies was 3 per cent. Many of these cases occurred in patients in whom the diagnosis was unsuspected. Only with the use of the appropriate stains was the diagnosis established. It is suggested that histological staining for amyloid should be performed routinely if cases are not to be missed. Attention is drawn to the epithelial spicular deposits with silver stains, that may be found in some cases. Five cases are presented in which there was evidence of regression of amyloidosis. These were all cases of secondary amyloidosis in whom improvement coincided with adequate treatment of the underlying pathology. It is suggested that energetic treatment of chronic inflammatory disease causing amyloidosis may be effective in preventing progessive renal damage, providing that renal function is not too severely impaired. Twenty-four of the 48 patients had some degree of hypertension (B.P. diastolic more than 90 mmHg) at some stage of the disease. The importance of adequate control of hypertension together with its frequency in amyloid disease is stressed. Other complicating factors of renal amyloid disease, such as fluid depletion and renal vein thrombosis, are discussed. Detailed post-mortem studies on 17 patients are presented. Although there was histological evidence of widespread infiltration throughout the body, clinical evidence of organs other than the kidney being involved was found in few instances. Six cases have been followed for more than five years after the histological diagnosis of renal amyloid was made. It is suggested that if due attention is paid to the control of the underlying pathology, early control of blood-pressure, and the proper management of the usual complications of renal disease, the prognosis of renal amyloidosis need not be as grave as hitherto suspected.

Studies on serum streptomycin concentrations by intrauterine electrophoresis with streptomycin

A study was made of streptomycin concentrations in blood serum after intrauterine electrophoresis of streptomycin and hyaluronidase is applied for the treatment of chronic inflammatory disease of the adnexa. It was established that concentration of streptomycin in the blood serum was low after hydrotubation. The concentration was sufficient to achieve bacteriostatic effect after intrauterine electrophoresis. Favorable results were obtained regarding the use of intrauterine electrophoresis with streptomycin and hyaluronidase in clinical treatment of some forms of inflammatory diseases of the internal genitals.

Treatment of chronic inflammatory diseases of the cervix with diathermocoagulation

One of the difficult parts of gynaecology in the field of conservative therapy is the treatment of endocervicitis and cervical erosions. Having established an accurate topical diagnosis of the disease, we proceeded to treatment. Below we analyse the treatment of 86 such patients, of whom 42 cases of endocervicitis and inflammatory cervical erosions were treated with diathermy or electrocoagulation.

The value of vaccine treatment of chronic inflammatory disease of the accessory sinuses of the nose

The LaryngoscopeVolume 20, Issue 9 p. 851-859 Article The value of vaccine treatment of chronic inflammatory disease of the accessory sinuses of the nose† H. S. Birkett M. D., H. S. Birkett M. D. 252 Mountain Street, MontrealSearch for more papers by this authorJ. C. Meakins M. D., J. C. Meakins M. D. 252 Mountain Street, MontrealSearch for more papers by this author H. S. Birkett M. D., H. S. Birkett M. D. 252 Mountain Street, MontrealSearch for more papers by this authorJ. C. Meakins M. D., J. C. Meakins M. D. 252 Mountain Street, MontrealSearch for more papers by this author First published: September 1910 https://doi.org/10.1288/00005537-191009000-00001 † Read at the Joint Meeting of the American Laryngological, Amerioan Climatological and American Otological Societies, Washington, D. C., May 4, 1910 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume20, Issue9September 1910Pages 851-859 RelatedInformation

On the Treatment of Chronic Inflammatory Diseases of the Larynx

On the Treatment of Chronic Inflammatory Diseases of the Larynx