f Acquiring iron (Fe) is critical to the metabolism and growth of Mycobacterium tuberculosis. Disruption of Fe metabolism is a potential approach for novel antituberculous therapy. Gallium (Ga) has many similarities to Fe. Biological systems are often unable to distinguish Ga 3؉ from Fe 3؉ . Unlike Fe 3؉ , Ga 3؉ cannot be physiologically reduced to Ga 2؉ . Thus, substituting Ga for Fe in the active site of enzymes may render them nonfunctional. We previously showed that Ga inhibits growth of M. tuberculosis in broth and within cultured human macrophages. We now report that Ga(NO 3 ) 3 shows efficacy in murine tuberculosis models. BALB/c SCID mice were infected intratracheally with M. tuberculosis, following which they received daily intraperitoneal saline, Ga(NO 3 ) 3 , or NaNO 3 . All mice receiving saline or NaNO 3 died. All Ga(NO 3 ) 3 -treated mice survived. M. tuberculosis CFU in the lungs, liver, and spleen of the NaNO 3 -treated or saline-treated mice were significantly higher than those in Ga-treated mice. When BALB/c mice were substituted for BALB/c SCID mice as a chronic (nonlethal) infection model, Ga(NO 3 ) 3 treatment significantly decreased lung CFU. To assess the mechanism(s) whereby Ga inhibits bacterial growth, the effect of Ga on M. tuberculosis ribonucleotide reductase (RR) (a key enzyme in DNA replication) and aconitase activities was assessed. Ga decreased M. tuberculosis RR activity by 50 to 60%, but no additional decrease in RR activity was seen at Ga concentrations that completely inhibited mycobacterial growth. Ga decreased aconitase activity by 90%. Ga(NO 3 ) 3 shows efficacy in murine M. tuberculosis infection and leads to a decrease in activity of Fe-dependent enzymes. Additional work is warranted to further define Ga's mechanism of action and to optimize delivery forms for possible therapeutic uses in humans.

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Objective Airway inflammatory patterns in older asthmatics are poorly understood despite high asthma-related morbidity and mortality. In this study, we sought to define the relationship between exposure to traffic pollutants, biomarkers in induced sputum, and asthma control in older adults. Methods Induced sputum was collected from 35 non-smoking adults ≥65 years with a physician’s diagnosis of asthma and reversibility with a bronchodilator or a positive methacholine challenge. Patients completed the Asthma Control Questionnaire (ACQ), and Elemental Carbon Attributable to Traffic (ECAT), a surrogate for chronic diesel particulate exposure, was determined. Equal numbers of subjects with high (≥0.39 µg/m3) versus low (<0.39 µg/m3) ECAT were included. Differential cell counts were performed on induced sputum, and myeloperoxidase (MPO) and eosinophil peroxidase (EPO) were measured in supernatants. Regression analyses were used to evaluate the relationship between sputum findings, ACQ scores, and ECAT. Results After adjustment for potential confounders, subjects with poorly controlled asthma based on ACQ ≥ 1.5 (n = 7) had significantly higher sputum eosinophils (median = 4.4%) than those with ACQ < 1.5 (n = 28; eosinophils = 2.6%; β = 10.1 [95% CI = 0.1–21.0]; p = 0.05). Subjects with ACQ ≥ 1.5 also had significantly higher sputum neutrophils (84.2% versus 65.2%; β = 7.1 [0.2–14.6]; p = 0.05). Poorly controlled asthma was associated with higher sputum EPO (β = 2.4 [0.2–4.5], p = 0.04), but not MPO (p = 0.9). High ECAT was associated with higher eosinophils (β = 10.1 [1.8–18.4], p = 0.02) but not higher neutrophils (p = 0.6). Conclusions Poorly controlled asthma in older adults is associated with eosinophilic and neutrophilic inflammation. Chronic residential traffic pollution exposure may be associated with eosinophilic, but not neutrophilic inflammation in older asthmatics.

Mycobacterium avium (M. avium) causes significant pulmonary infection, especially in immunocompromised hosts. Alveolar macrophages (AMs) represent the first line of host defense against infection in the lung. Interferon gamma (IFN‐γ) activation of AMs enhances in vitro killing of pathogens such as M. avium. We hypothesized that airway delivery of AMs into the lungs of immunodeficient mice infected with M. avium will inhibit M. avium growth in the lung and that this macrophage function is in part IFN‐γ dependent. In this study, normal BALB/c and BALB/c SCID mice received M. avium intratracheally while on mechanical ventilation. After 30 days, M. avium numbers increased in a concentration‐dependent manner in SCID mice compared with normal BALB/c mice. Airway delivery of IFN‐γ‐activated BALB/c AMs or J774A.1 macrophages overexpressing IFN‐γ into the lungs of SCID mice resulted in a significant decrease in M. avium growth (P < 0.01, both comparisons) and limited dissemination to other organs. In addition, airway delivery of IFN‐γ activated AMs and macrophages overexpressing IFN‐γ increased the levels of IFN‐γ and TNF‐α in SCID mice. A similar protective effect against M. avium infection using J774A.1 macrophages overexpressing IFN‐γ was observed in IFN‐γ knockout mice. These data suggest that administration of IFN‐γ activated AMs or macrophages overexpressing IFN‐γ may partially restore local alveolar host defense against infections like M. avium, even in the presence of ongoing systemic immunosuppression.