Rux largely restores lungs in Iraq PM-exposed mice, Up-regulating regulatory T-cells (Tregs).

Background Military personnel post-deployment to Iraq and Afghanistan have noted new-onset respiratory illness. This study's primary objective was to further develop an animal model of Iraq Afghanistan War Lung Injury (IAW-LI) and to test a novel class of anti-injury drug called RuX. Methods Particulate Matter (PM) samples were obtained in Iraq then characterized by spectromicroscopy. C57BL/6 mice underwent orotracheal instillation with PM, followed by drinkable treatment with RuX. Lung histology, inspiratory capacity (FlexiVent), thymic/splenic regulatory T cell (Treg) number, and whole-lung genomics were analyzed. Results Tracheal instillation of Iraq PM led to lung septate thickening and lymphocytic inflammation. PM-exposed mice had suppression of thymic/splenic regulatory T-cells (Tregs). Drinking RuX after PM exposure attenuated the histologic lung injury response, improved lung inspiratory capacity, and increased Tregs. Pooled whole lung genomics suggest differences among gene expression of IL-15 among control, PM, and PM + RuX groups. Conclusions RuX, a ruthenium and alpha-lipoic acid complex, attenuates lung injury by improving histology and inspiratory capacity via upregulation of Tregs in Iraq PM-exposed C57BL/6. Plausible genomic effects may involve IL-15 whole lung gene expression.

VIP Regulates the Development & Proliferation of Treg in vivo in spleen.

BACKGROUND: Mounting evidence supports a key role for VIP as an anti-inflammatory agent and promoter of immune tolerance. It suppresses TNF-α and other inflammatory cytokines and chemokines, upregulates anti-inflammatory IL-10, and promotes immune tolerant cells called T regulatory (Treg) cells. VIP KO mice have recently been demonstrated to have spontaneous airway and pulmonary perivascular inflammatory responses, as part of asthma-like and pulmonary hypertension phenotypes, respectively. Both inflammatory responses are correctable with VIP. Focusing on this model, we have now investigated the influence of VIP not only on inflammatory cells but also on Treg cells. METHODS: Using flow cytometric analysis, we examined the relative preponderance of CD25+CD4+ cells and anti-inflammatory Treg cells, in extracts of thymus and spleen from VIP KO mice (5 VIP KO; 5 VIP KO+ VIP; 10 wild-type). This method allowed antibody-based flow cytometric identification of Treg cells using surface markers CD25 and CD4, along with the: 1) intracellular activation marker FoxP3; and 2) Helios, which distinguishes cells of thymic versus splenic derivation. CONCLUSIONS: Deletion of the VIP gene results in: 1) CD25+CD4- cell accumulation in the thymus, which is corrected by VIP treatment; 2) more Treg in thymus lacking Foxp3 expression, suggesting VIP is necessary for immune tolerance; and, 3) a tendency towards deficiency of Treg cells in the spleen, which is normalized by VIP treatment. Treg lacking Helios are induced by VIP intrasplenically rather than by migration from the thymus. These results confirm the dual role of VIP as an anti-inflammatory and immune tolerance-promoting agent.

Iraq dust is respirable, sharp, and metal-laden and induces lung inflammation with fibrosis in mice via IL-2 upregulation and depletion of regulatory T cells.

OBJECTIVES: Determine whether surface dust grab samples taken from a large military base in Iraq are toxic and respirable. METHODS: X-ray diffraction for mineral content, x-ray fluorescence for elemental content, in vivo mouse dust challenges for assessment of histological changes, bronchoalveolar lavage for cytokines, polarizing light microscopy for crystals in lung tissue, and Fluorescence Activated Cell Sorting for cell surface and intracellular markers were utilized. RESULTS: Camp Victory, Iraq dust taken during wartime contains respirable particles 2.5 microns in size, constituting particulate matter air pollution. Dust particles are angular and have sharp edges. Trace metals (including titanium) calcium and silicon are present. Mice with airway instillation of dust have polarizable crystals in lung and septate inflammation. Regulatory T cells (CD4⁺CD25⁺FOXP3⁺) are decreased in thymus and spleen. Interleukin-2 (IL-2) is upregulated in bronchoalveolar lavage. CONCLUSIONS: Respirable Iraq dust leads to lung inflammation in mice similar to that seen in patients with polarizable crystals, which seem to be titanium.