Inhalable microparticles modify cytokine secretion by lung macrophages of infected mice
Rolee Sharma1, Awadh Bihari Yadav, Pavan Muttil
1Pharmaceutics Division, Central Drug Research Institute, CSIR, Lucknow 226001, India.
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.
Insights
Inhaled microparticles with tuberculosis drugs isoniazid (INH) and rifabutin (RFB) significantly altered lung cytokine profiles, enhancing anti-inflammatory responses and contributing to treatment efficacy. This delivery method shows promise for tuberculosis (TB) management.
Area of Science:
- Immunology
- Pharmacology
- Infectious Diseases
Background:
- Tuberculosis (TB) remains a global health challenge, necessitating novel treatment strategies.
- Inhalable microparticles offer a promising drug delivery system for pulmonary infections like TB.
- Understanding the immunomodulatory effects of inhaled therapies is crucial for optimizing treatment outcomes.
Purpose of the Study:
- To investigate the impact of inhaled isoniazid (INH) and rifabutin (RFB) microparticles on the lung cytokine environment in a mouse model of Mycobacterium tuberculosis (Mtb) infection.
- To compare the cytokine secretion profiles of lung macrophages following different drug administration routes (inhalation vs. oral gavage).
- To correlate observed cytokine changes with the efficacy of inhaled microparticle therapy against experimental TB.
Main Methods:
- Mice were infected with Mtb H37Ra and treated with oral INH/RFB, inhaled INH/RFB microparticles, or inhaled microparticles alone.
- Bronchoalveolar lavage (BAL) was performed to collect lung macrophages.
- BAL fluid and macrophage culture supernatants were analyzed for key cytokines (TNF-α, IFN-γ, IL-12, IL-10) using ELISA.
Main Results:
- Inhaled microparticles significantly enhanced TNF-α and supported IFN-γ secretion, even with increased IL-10.
- Oral chemotherapy led to increased IL-12 and decreased TNF-α.
- Distinct cytokine profiles emerged based on drug delivery method, suggesting varied impacts on host immune responses.
Conclusions:
- Inhaled INH/RFB microparticles modulate the lung immune environment differently than oral administration.
- These immunomodulatory effects may contribute to the superior efficacy observed with inhaled microparticle therapy for experimental TB.
- Drug delivery route significantly influences the host-pathogen-drug interaction in tuberculosis treatment.
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