minocycline and Asthma

We previously reported that minocycline treatment of allergic asthmatic patients had oral steroid sparing effects and improved their clinical status and that minocycline suppressed in vitro induction of IgE responses by their PBMC. The effect of minocycline on human or animal IgE responses in vivo has not been studied. Allergic asthmatics (serum IgE: 505 +/- 535 IU ml(-1)) were given minocycline (150 mg po to 250 mg po BID) as add-on therapy to standard care for up to 10 months; control subjects (IgE: 405 +/- 472 IU ml(-1)) received standard care (n = 6 per group). Serum immunoglobulin (IgM, IgG, IgE and IgA) levels were determined monthly (Nephelometry, Unicap Total IgE Fluoroenzyme immunoassay). BALB/c mice (n = 6 per group) were injected intraperitoneally with benzylpenicilloyl(14)-Keyhole limpet hemocyanin (BPO(14)-KLH) in alum on days 0, 21 and 42, fed with minocycline or doxycycline (10-100 mg kg(-1)) on day 44 and numbers of BPO-specific IgG(1), IgE and IgA antibody-forming cell (AFC) in mesenteric LN and spleen and serum immunoglobulin levels were determined on days 46-70 (enzyme-linked immunosorbent spot assay, ELISA). The ability of minocycline or doxycycline to suppress in vitro induction of murine memory IgE responses also was investigated. Minocycline strongly suppressed serum IgE levels of allergic asthmatics (9% per month) (P = 0.012). Minocycline (and doxycycline) also strongly suppressed peak murine IgE AFC and serum IgE responses (>95, approximately 75%, respectively) and in vitro induction of memory IgE responses by murine mesenteric LN and spleen cells (>95%). Tetracycline suppression of all human and murine IgE responses was IgE isotype specific. Suppression of murine IgE responses in vivo was dose dependent and lasted 5-7 days.

Topics: Adult; Aged; Animals; Anti-Allergic Agents; Asthma; Cells, Cultured; Doxycycline; Female; Hemocyanins; Humans; Immunoglobulin E; Immunologic Memory; Lymph Nodes; Male; Mesentery; Mice; Mice, Inbred BALB C; Middle Aged; Minocycline; Penicillin G; Spleen; Treatment Outcome; Young Adult

Minocycline protects against asthma independently of its antibiotic function and was recently reported as a potent poly(ADP-ribose) polymerase (PARP) inhibitor. In an animal model of asthma, a single administration of minocycline conferred excellent protection against ovalbumin-induced airway eosinophilia, mucus hypersecretion, and Th2 cytokine production (IL-4/IL-5/IL-12(p70)/IL-13/GM-CSF) and a partial protection against airway hyperresponsiveness. These effects correlated with pronounced reduction in lung and sera allergen-specific IgE. A reduction in poly(ADP-ribose) immunoreactivity in the lungs of minocycline-treated/ovalbumin-challenged mice correlated with decreased oxidative DNA damage. The effect of minocycline on PARP may be indirect, as the drug failed to efficiently block direct PARP activation in lungs of N-methyl-N'-nitro-N-nitroso-guanidine-treated mice or H(2)O(2)-treated cells. Minocycline blocked allergen-specific IgE production in B cells potentially by modulating T cell receptor (TCR)-linked IL-4 production at the mRNA level but not through a modulation of the IL-4-JAK-STAT-6 axis, IL-2 production, or NFAT1 activation. Restoration of IL-4, ex vivo, rescued IgE production by minocycline-treated/ovalbumin-stimulated B cells. IL-4 blockade correlated with a preferential inhibition of the NF-κB activation arm of TCR but not GSK3, Src, p38 MAPK, or ERK1/2. Interestingly, the drug promoted a slightly higher Src and ERK1/2 phosphorylation. Inhibition of NF-κB was linked to a complete blockade of TCR-stimulated GATA-3 expression, a pivotal transcription factor for IL-4 expression. Minocycline also reduced TNF-α-mediated NF-κB activation and expression of dependent genes. These results show a potentially broad effect of minocycline but that it may block IgE production in part by modulating TCR function, particularly by inhibiting the signaling pathway, leading to NF-κB activation, GATA-3 expression, and subsequent IL-4 production.

Topics: Animals; Asthma; GATA3 Transcription Factor; Gene Expression Regulation; Immunoglobulin E; Immunologic Factors; Inflammation; Interleukin-4; Male; Mice; Mice, Inbred C57BL; Minocycline; NF-kappa B; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Receptors, Antigen, T-Cell; Signal Transduction

We have recently found that the tetracycline minocycline suppresses inflammatory responses in serum immunoglobulin (Ig)E-positive asthmatic patients, and that IgE levels can decrease in these patients. The mechanism by which minocycline suppresses these responses is unknown.. We have now investigated the ability of the tetracyclines, minocycline and doxycycline, to regulate IgE responses of peripheral blood mononuclear cells (PBMC) obtained from serum IgE-positive asthmatic patients.. The distributions of CD3+, CD4+, CD8+, and CD19+ lymphocytes in peripheral blood of serum IgE-positive asthmatic patients and IgE-negative nonasthmatic controls, and cytokine-specific mRNA expression by their PBMC were determined by flow cytometry (reverse transcriptase-polymerase chain reaction). Serum Ig levels also were determined (nephelometry, fluoroenzymeimmunoassay, enzyme-linked immunoadsorbent assay; n = 7/group). PBMC (1.5 x 10(6)/mL) were cultured with anti-CD40 monoclonal antibody and recombinant human interleukin-4 in the presence/absence of minocycline or doxycycline (0.1 to 10 microg/mL), and IgE levels in supernatants determined on days 0, 3, and 10 (enzyme-linked immunoadsorbent assay).. Asthmatic and nonasthmatic subjects had similar numbers of blood CD4+ T cells (779/mm3 +/- 73 and 766 +/- 115, respectively) and CD19+ B-cells (239/mm3 +/- 35 and 379 +/- 95, respectively); however, CD8+ T cell numbers were decreased in asthmatic compared with nonasthmatic subjects (378/mm3 +/- 66 and 568 +/- 53, respectively; P = 0.045). High IgE levels were detected in supernatants of asthmatic PBMC on day 10 (28 ng/mL +/- 12), whereas control IgE levels did not change (<2.5 ng/mL). When either minocycline or doxycycline was included in culture, IgE production by asthmatic PBMC was strongly suppressed in dose-dependent fashion on day 10 (>80% with 10 microg/mL); control IgE did not change (<2.5 ng/mL).. The results are consistent with the idea that the therapeutic benefits obtained by asthmatic patients from minocycline may, in part, result from IgE suppression.

Topics: Adult; Anti-Asthmatic Agents; Asthma; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Doxycycline; Female; Humans; Immunoglobulin E; Leukocytes, Mononuclear; Lymphocyte Count; Lymphocyte Subsets; Male; Middle Aged; Minocycline; RNA, Messenger

Topics: Adult; Anti-Bacterial Agents; Asthma; Conjunctiva; Drug Hypersensitivity; Female; Humans; Hypereosinophilic Syndrome; Minocycline

Minocycline has been identified as a pathogenic agent in drug-induced pneumonia. We report a new case.. A 38-year-old female asthmatic patient was given minocycline (100 mg/j) for facial acne. She was allergic to penicillin. Other treatments were theophylline, salbutamol and inhaled budesonide. Severe bilateral hypoxemia pneumonia developed with high eosinophil blood counts within a few days of treatment onset. The lung disease regressed with minocycline withdrawal.. This case is exceptional because the minocycline-induced lung disease continued to progress despite high-dose corticosteroids in this asthmatic patient.

Topics: Adult; Anti-Bacterial Agents; Asthma; Female; Humans; Lung Diseases, Interstitial; Minocycline

We report a case of minocycline-induced pneumonitis. A 30-year-old woman was treated with minocycline for mycoplasma pneumonia of the right upper lobe. About 15 days after starting treatment, she developed a productive cough, stridor, and dyspnea. The chest X-ray film showed pulmonary infiltration in the left middle lung field. Based on the clinical history and the detection of eosinophilia in the bronchoalveolar fluid, drug-induced pneumonitis was suspected. Treatment with minocycline was discontinued and prednisolone (20 mg/day) was started, after which her symptoms subsided and there was marked regression of the pulmonary infiltrates on chest X-ray films. The lymphocyte stimulation test for minocycline was negative, but the diagnosis was confirmed by a positive oral provocation test.

Topics: Adult; Asthma; Drug Hypersensitivity; Female; Humans; Minocycline; Pneumonia; Respiratory Hypersensitivity

Topics: Asthma; Bronchitis; Drug Tolerance; Female; Humans; Minocycline; Tetracycline; Vertigo; Vestibule, Labyrinth

Topics: Adult; Asthma; Bronchitis; Chronic Disease; Dose-Response Relationship, Drug; Haemophilus influenzae; Humans; Infusions, Parenteral; Kidney; Liver; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Sputum; Staphylococcus; Tetracycline; Tetracyclines