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Endogenous lung stem cells and contribution to disease.

J Pathol. 2008 Oct 16;

Authors: Snyder J, Teisanu R, Stripp B

Epithelial branching during the process of lung development results in the establishment of distinct functional zones, each of which is characterized by a unique cellular composition and repertoire of local progenitor cells. Significant new insights into cellular and molecular mechanisms of epithelial maintenance that provide insights into the pathophysiology of lung disease have been made in recent years. This review focuses on the complex structure-function relationship in the airway epithelium, how this epithelium is maintained in the normal state and repaired following injury, and how deregulation may contribute to airway disease and cancer. Copyright (c) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PMID: 19039828 [PubMed - as supplied by publisher]

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CXCR3-deficiency protects influenza-infected CCR5-deficient mice from mortality.

Eur J Immunol. 2008 Nov 27;38(12):3376-3387

Authors: Fadel SA, Bromley SK, Medoff BD, Luster AD

Mice lacking the chemokine receptor CCR5 are susceptible to mortality from a normally non-lethal influenza infection. Here we found that CXCR3-deficiency rescued CCR5-deficient (CCR5(-/-)) mice from influenza-induced mortality. The number of mononuclear phagocytes in the airways was transiently increased in CCR5(-/-) mice but not in CXCR3-CCR5 double-deficient mice. Antigen-specific CXCR3-CCR5 double-deficient CD8 effector cells were less efficient at entering the airways compared with WT or CCR5(-/-) CD8 effector cells. The decrease in inflammatory cell infiltrates in CXCR3-CCR5 double-deficient-infected mice correlated with a decrease in CCL2 and IFN-gamma production in the airways. Finally, CXCR3-CCR5 double-deficient mice that survived the primary viral challenge were protected from a lethal secondary challenge, indicating that T-cell-mediated protective memory was not compromised in mice lacking these chemokine receptors. In conclusion, CXCR3-deficiency attenuated the lethal cellular immune response in CCR5(-/-) influenza-infected mice without hindering viral clearance or long-term immunity.

PMID: 19039768 [PubMed - as supplied by publisher]

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PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release.

Science. 2008 Nov 28;322(5906):1392-5

Authors: Singh R, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, Dowd CS, Lee IY, Kim P, Zhang L, Kang S, Keller TH, Jiricek J, Barry CE

Bicyclic nitroimidazoles, including PA-824, are exciting candidates for the treatment of tuberculosis. These prodrugs require intracellular activation for their biological function. We found that Rv3547 is a deazaflavin-dependent nitroreductase (Ddn) that converts PA-824 into three primary metabolites; the major one is the corresponding des-nitroimidazole (des-nitro). When derivatives of PA-824 were used, the amount of des-nitro metabolite formed was highly correlated with anaerobic killing of Mycobacterium tuberculosis (Mtb). Des-nitro metabolite formation generated reactive nitrogen species, including nitric oxide (NO), which are the major effectors of the anaerobic activity of these compounds. Furthermore, NO scavengers protected the bacilli from the lethal effects of the drug. Thus, these compounds may act as intracellular NO donors and could augment a killing mechanism intrinsic to the innate immune system.

PMID: 19039139 [PubMed - in process]

Modulation of dendritic cell function by cowshed dust extract.

Innate Immun. 2008 Dec;14(6):345-55

Authors: Gorelik L, Kauth M, Gehlhar K, Bufe A, Holst O, Peters M

We have shown previously that inhalation of cowshed dust extract (CDE) resulted in decreased airway reactivity, eosinophilic inflammation and sensitization in a mouse model of allergic asthma. Our data suggested down-regulation of allergic immune response rather than activation of a Th1 response towards the model allergen. However, the precise mechanism of allergy protection is not yet understood in detail. To gain deeper insight into CDE-induced immune modulation, we have analysed the effects of CDE on dendritic cell biology. Dendritic cells were generated from murine bone marrow cells (BMDC). Cells were stimulated with CDE and subsequently used to sensitize mice via the airways. Our results showed that cells were not able to prime mice for allergic immune response when they were treated with CDE 2 days before pulsing with allergen, whereas cells that were stimulated with CDE simultaneously to OVA pulsing induced a fully developed allergic immune response. Surprisingly, CDE-treated cells that were not able to prime mice for allergic immune response exhibit an activated phenotype with high expression of the co-stimulatory surface molecule CD86. Moreover, CDE-treated cells transiently produced high amounts of cytokines such as IL-10, IL-12p70 and TNF-alpha. Interestingly, blocking of autocrine-produced IL-10 in vitro partially restored the allergy-inducing capacity of CDE-exposed cells. Thus, we conclude that prolonged exposure to CDE reduces the allergy-inducing capacity of dendritic cells. Furthermore, we present evidence that an autocrine IL-10 dependent mechanism seems to be involved in down-regulation of dendritic cell function due to stimulation with CDE.

PMID: 19039058 [PubMed - in process]

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Lycopene incorporation into egg yolk and effects on laying hen immune function.

Poult Sci. 2008 Dec;87(12):2573-80

Authors: Olson JB, Ward NE, Koutsos EA

Carotenoids are partially responsible for the colors of plants and when consumed by humans and animals are deposited into tissues (e.g., skin and egg yolk in laying hens) and may have health benefits. Because carotenoids are more available when consumed from egg yolk sources than vegetables, this research examined the ability of the laying hen to deposit dietary lycopene, a carotenoid that imparts red color in tomatoes, into the egg yolk and to investigate effects on immune function. All birds were housed in commercial cages, had ad libitum access to water, and were fed 100 g/bird per day. Experiment 1 consisted of 4 dietary concentrations of lycopene (0, 65, 257, and 650 mg of lycopene/kg of diet). High-performance liquid chromatography analysis confirmed that dietary lycopene was incorporated into egg yolks. Experiment 2 was a completely randomized design, with 3 concentrations of lycopene (0, 420, and 840 mg of lycopene/kg of diet) and 6 concentrations of alpha-tocopherol (0, 84, 164, 200, 284, and 364 mg of alpha-tocopherol/kg of diet). Egg yolk lycopene (P < 0.05) and vitamin E (P < 0.05) were increased with increasing dietary concentrations, whereas lutein and zeaxanthin concentrations remained constant. Immune responses (inflammatory, cutaneous basophil hypersensitivity, 1 degrees and 2 degrees antibody response) were induced but were not affected by dietary lycopene or vitamin E. These data indicate that lycopene can be incorporated into egg yolks, and at these dietary concentrations, alpha-tocopherol and lycopene may not affect the immune system of the laying hen.

PMID: 19038813 [PubMed - in process]