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    • In Pichavant et al used week CS

    2018-10-30

    In , Pichavant et al. used 12week CS exposure to generate mice with COPD-like lung disease (). There was increased neutrophilic inflammation and bacterial load after exposure in CS compared to room air (RA) exposed mice. Furthermore, there were lower IL-17 and IL-22 levels in infected CS-exposed mice, and lower levels of the Th17 inducers IL-1β and IL-23 produced by APCs. The suppressive effect of CS on various cytokines has also been observed in previous human studies using COPD lung cells, such as macrophages (). IL-22 administration before bacterial challenge increased bacterial clearance in CS exposed mice. There was no change in lung neutrophil numbers, but there were increased levels of anti-microbial peptides and IL-17 production, and less histological evidence of associated lung damage. IL-17 was not administered to combat bacterial infection, as this cytokine may contribute to COPD pathophysiology (). These results strongly suggest a role for IL-22 in promoting anti-bacterial immunity in the context of chronic cigarette smoke exposure. Experiments using peripheral blood mononuclear diprenorphine manufacturer showed defective IL-17 and IL-22 secretion from COPD compared to control cells after exposure to , providing validation of mouse model results by using relevant cells from patients with disease. These studies by Roos et al. () and Pichavant et al. () provide potentially important insights into the complex interactions between Th17 cytokines, neutrophilia and bacterial exposure in COPD. In CS-exposed mice, NTHi and infection both caused enhanced lung neutrophilia, but IL-17 production was enhanced with the former and decreased with the latter. There may be differences between the experimental details of the mouse CS exposure protocols, such as duration of CS exposure, that could alter the responses to bacteria. However, in both CS models the neutrophilic response was increased by bacterial exposure, but the IL-17 response was bacterial species dependent. Furthermore, both papers convincingly back up mouse data with results from COPD patients. Where does this leave us with the potential for targeting IL-17, given its potential pro-inflammatory role in COPD? It seems that suppressing IL-17 may be a useful anti-inflammatory approach in the context of NTHi infection, but not during infection. Would pharmacological modulation of IL-22 be beneficial in COPD patients? There appears to be a defect in the IL-22 response to in COPD patients, and animal model data suggests that modulating IL-22 levels improves bacterial clearance and inflammation in a manner that does not involve any change in neutrophil numbers (). It would be important to know if this defect in IL-22 production is also present after exposure to NTHi in COPD patients and animal models. We are becoming increasingly aware of the heterogeneous nature of COPD, with specific treatments being required for subsets of patients with distinct characteristics (). The endotype concept, a group of patients defined by a biological mechanism, allows pharmacological targeting of mechanisms rather than clinical characteristics (). Targeting the defective IL-22 response to would be an example of endotype-driven treatment. Targeting the excessive IL-17 response to NHTi would be another example. The therapeutic index (benefit versus risk) of such approaches will be enhanced by definition of the patients most likely to benefit. As we move into the era of personalised medicine, one size will not fit all in COPD. Disclosure
    Iron is an essential element for most prokaryotes and all eukaryotes. Iron is required for heme synthesis, iron–sulfur cluster synthesis and as a co-factor for a wide variety of enzymes. Most of the iron in vertebrates is found in hemoglobin in red blood cells and iron deficiency anemia is a significant medical problem. Iron, however, is found in all cells and iron deficiency is the most common nutritional deficiency in the world reportedly affecting two billion people (), particularly affecting young children and women (). While the consequences of iron deficiency can be readily seen in cultured cells, the consequences of iron deficiency on specific tissues have been harder to define, largely due to the overwhelming systemic defects of iron-limited erythropoiesis. The ability to generate cell-specific genetic deletions in mice has permitted the analysis of iron-limitation on specific cell types in the absence of systemic iron deficiency. In vertebrates elemental iron enters cells through different transport systems. Iron exported through the absorptive intestinal cells is bound in plasma to transferrin (Tf) where it is delivered to cells that require it as shown by the expression of transferrin receptor 1 (Tfr1) on those cells. Cell types with the highest expression of Tfr1 include erythroid precursors and dividing cells. When the iron binding sites on Tf are occupied or when Tf is absent iron introduced into plasma can enter cells through other transport systems ().