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<b>Background:</b> Altered iron metabolism is associated with COPD pathogenesis, and elevated iron levels are observed in the COPD lung. COPD is also associated with elevated levels of senescent cells that contain increased intracellular iron. Whether this is a cause or consequence of senescence is unknown. <b>Aim:</b> To examine the relationship between excess intracellular iron and senescence in COPD. <b>Methods:</b> Total intracellular iron was detected in small airway epithelial cells (SAEC) from non-smokers (NS) and COPD patients by atomic absorbance spectrometry. Heme iron was measured using absorbance at 400 nM. SAEC were treated with ferric ammonium iron citrate (FAC) or the iron chelator, deferoxamine. Iron and senescence markers were detected by western blot. <b>Results:</b> Intracellular iron was increased 1.7-fold (p=0.002) and heme iron 2.1-fold in COPD SAEC compared NS cells (n=6 p=0.008). Treatment of NS and COPD SAEC with FAC induced a 3.65 (p=0.4) and 4.8-fold (p=0.02) increase in iron respectively, with COPD SAEC accumulating significantly more iron than NS cells (n=6 p=0.04). Iron chelation significantly reduced intracellular iron in COPD, but not NS SAEC (n=4 p=0.02). Elevated expression of transferrin heavy chain and transferrin receptor were detected in COPD SAEC compared to NS, correlating with alterations in senescence markers p21 and Sirtuin-1/-6 (n=6). <b>Conclusion:</b> Elevated levels of intracellular iron were observed in COPD SAEC compared to NS, with COPD SAEC having increased capacity to accumulate extracellular iron, possibly via increased transferrin receptor. Altered senescence markers were also seen in COPD, but whether altered iron metabolism regulates this requires further investigation.
No abstract is provided for this article.
No abstract is provided for this article.
The effect of coronary artery bypass graft (CBG) on left ventricular performance was evaluated by analysing preoperative (preop) and postoperative (postop) pressure-derived measurements from tip manometers during atrial pacing stress (APS) and resting segmental wall motion (SWM) of 50 patients (pts), restudied 12 months after CBG. Preoperatively, graft flow and reactive hyperemia (RH) were also measured. End diastolic pressure (EDP) maximal velocity of contractile element (Vmax) during APS, mean velocity of circumferential fiber shortening (Vcf) and SWM at rest were compared in three groups: Gr I, 13 pts with postop increase (+5 p. 100) of ejection fraction (EF); Gr II, 16 pts with EF decreased (-5 p. 100); Gr III, 21 pts with EF unchanged (+/- 4 p. 100). At rest, EDP of Gr II was the only parameter significantly altered with a postop increase of 5 mmHg (< 0.05). During APS, Vmax postop is increased in Gr I (59.5 s-1 preop, 67.5 postop, p < 0.02) while it is decreased in Gr II (67 s-1 preop, 57 postop, p < 0.05) and unchanged in Gr III. At rest, consistent changes in mean Vcf were found in Gr I (0.69 length/s preop, 0.97 postop, p < 0.001) and Gr II (0.87 preop, 0.68 postop, p < 0.001). In Gr I, regional improvement in wall motion was equally distributed to the anterior and posterior wall. In Gr II postop reduction of regional shortening was confined to the anterior wall. In Gr II successful revascularization of the anterior wall was performed only in 55 p. 100 of pts versus p. 100 in Gr I. In addition, during RH, peak diastolic flow was significantly higher (p < 0.05) in Gr I (341 +/- 63 ml) than in Gr II (197 +/- 34) underlining the higher level of effective revascularization attained in GrI. We conclude that resting regional and global ejection phase indices as well isovolumic phase indices during stress will improve when complete revascularization procedure is successful.
Multiple kinases play a critical role in orchestrating the chronic inflammation and structural changes in the respiratory tract of patients with asthma and chronic obstructive pulmonary disease (COPD). Kinases activate signaling pathways that lead to contraction of airway smooth muscle and release of inflammatory mediators (such as cytokines, chemokines, growth factors) as well as cell migration, activation, and proliferation. For this reason there has been great interest in the development of kinase inhibitors as anti-inflammatory therapies, particular where corticosteroids are less effective, as in severe asthma and COPD. However, it has proven difficult to develop selective kinase inhibitors that are both effective and safe after oral administration and this has led to a search for inhaled kinase inhibitors, which would reduce systemic exposure. Although many kinases have been implicated in inflammation and remodeling of airway disease, very few classes of drug have reached the stage of clinical studies in these diseases. The most promising drugs are p38 MAP kinases, isoenzyme-selective PI3-kinases, Janus-activated kinases, and Syk-kinases, and inhaled formulations of these drugs are now in development. There has also been interest in developing inhibitors that block more than one kinase, because these drugs may be more effective and with less risk of losing efficacy with time. No kinase inhibitors are yet on the market for the treatment of airway diseases, but as kinase inhibitors are improved from other therapeutic areas there is hope that these drugs may eventually prove useful in treating refractory asthma and COPD.
1 We have explored in man the hypothesis that histamine released from dermal mast cells by neurotransmitters from afferent nerves contributes to vasodilatation of the axon reflex. 2 The ability of substance P to release histamine from human skin in vivo, and the effects of a histamine H1-receptor antagonist on capsaicin-induced axon reflex flares were studied. 3 Intradermal injections of substance P (50 pmol) produced a weal and flare response which was associated with increased histamine concentration in blood draining the site (mean plasma histamine concentration before injection 0.17 ± 0.02 ng ml−1 (± s.e.mean), concentration one minute after injection 1.26 ± 0.28 ng ml−1, n = 6). 4 Terfenadine, an H1-receptor antagonist, had no effect on the flare response to intradermal injection of capsaicin at a dose which inhibited by more than 60% the flare response to exogenous histamine and to histamine released from dermal mast cells by substance P. 5 Substance P releases histamine from human skin in vivo. However, whatever the nature of the neurotransmitter released from afferent nerves during the axon reflex, it does not produce vasodilatation through release of histamine from dermal mast cells. Histamine may still contribute to the flare by initiation of the reflex.
