title: Inhalable microparticles modify cytokine secretion by lung macrophages of infected mice.
abstract: Inhalable microparticles containing a large payload of isoniazid (INH) and rifabutin (RFB) in equal proportions show extremely high efficacy against experimental animal tuberculosis (TB). It was investigated whether inhaled microparticles affect the cytokine environment in the lung lumen, and cytokine secretion by airway and lung macrophages recovered from mice infected with Mycobacterium tuberculosis (Mtb). We attempted to determine whether the cytokine environment of the mouse lung receives significant contribution by lung macrophages, and whether these macrophages maintain a profile of cytokine secretion that is consistent with the cytokine environment of the lung. Groups of mice were infected intravenously with Mtb H37Ra and treated with (a) 5 mg/Kg each of INH and RFB administered by oral gavage; or, (b) 2.5 mg/Kg of the same and an additional ∼2.5 mg/Kg in the form of inhaled microparticles; or, (c) ∼2.5 mg/Kg by inhalation alone. Bronchioalveolar lavage (BAL) was carried out and recovered macrophages cultured. BAL Fluid and culture supernatants were assayed for tumor necrosis factor (TNF-α), interferon (IFN-γ), interleukin (IL)-12 and IL-10 by ELISA and amounts compared with both infected and uninfected, untreated controls. Inhaled microparticles enhanced secretion of TNF-α and supported IFN-γ secretion despite upregulated IL-10. Oral chemotherapy with the same drugs enhanced IL-12 and downregulated TNF-α. Differences in cytokine profiles suggest distinct effects of drug delivery modalities on innate immune strategies mobilized during host response. These differences might account, in part, for the extraordinary efficacy of the microparticles.
authors.affiliation: Pharmaceutics Division, Central Drug Research Institute, CSIR, Lucknow 226001, India.
authors.forename: Rolee
authors.initials: R
authors.lastname: Sharma
authors.forename: Awadh Bihari
authors.initials: AB
authors.lastname: Yadav
authors.forename: Pavan
authors.initials: P
authors.lastname: Muttil
authors.forename: Heikham
authors.initials: H
authors.lastname: Kajal
authors.forename: Amit
authors.initials: A
authors.lastname: Misra
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D007371:Interferon-gamma / Q000187:drug effects; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007538:Isoniazid / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000276:immunology; D017828:Rifabutin / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D017828:Rifabutin; D007371:Interferon-gamma; D007538:Isoniazid