Background Protamine neutralization is an essential step for the safe use and inactivation of the unfractionated heparin (UFH) that is widely employed in surgical and non-surgical procedures involving extracorporeal circulation. Objective To compare protamine neutralization of different pharmaceutical-grade UFHs prepared from porcine or bovine intestine (HPI and HBI, respectively). HBI has approximately half the anticoagulant potency of HPI, mostly as consequence of its fraction enriched with N-sulfated α-glucosamine disaccharides. Methods Protamine neutralization of HPI and HBI was evaluated with in vitro, ex vivo and in vivo assays. We also performed in-depth assessments of the complexation of protamine with these distinct UFHs by using nuclear magnetic resonance and mass spectroscopy. Results HPI and HBI interact similarly with protamine on a mass/mass basis; however, HBI requires more protamine than HPI to have its anticoagulant activity fully neutralized, because of its lower potency, which entails the use of higher doses. Nuclear magnetic resonance spectra revealed that HPI precipitates homogeneously with protamine. On the other hand, the low-sulfated fraction of HBI, enriched with N-sulfated α-glucosamine, precipitates at higher concentrations of protamine than the fraction more like HPI, with a preponderance of N,6-disulfated α-glucosamine disaccharides. Finally, mass spectroscopy spectra showed that some of the different peptide components of protamine interact preferentially with the heparins, irrespective of their animal origin. Conclusion Our results have important medical implications, indicating that protamine neutralization of HBI, determined exclusively by point-of-care coagulation assessments, must fail because of its lower-sulfated fraction with reduced anticoagulant activity that could remain in the circulation after the neutralization procedure.
Experimental studies have reported that aerobic exercise after asthma induction reduces lung inflammation and remodeling. Nevertheless, no experimental study has analyzed whether regular/moderate aerobic training before the induction of allergic asthma may prevent these inflammatory and remodeling processes. For this purpose, BALB/c mice (n = 96) were assigned into non-trained and trained groups. Trained animals ran on a motorized treadmill at moderate intensity, 30 min/day, 3 times/week, for 8 weeks, and were further randomized into subgroups to undergo ovalbumin sensitization and challenge or receive saline using the same protocol. Aerobic training continued until the last challenge. Twenty-four hours after challenge, compared to non-trained animals, trained mice exhibited: (a) increased systolic output and left ventricular mass on echocardiography; (b) improved lung mechanics; (c) decreased smooth muscle actin expression and collagen fiber content in airways and lung parenchyma; (d) decreased transforming growth factor (TGF)-β levels in bronchoalveolar lavage fluid (BALF) and blood; (e) increased interferon (IFN)-γ in BALF and interleukin (IL)-10 in blood; and (f) decreased IL-4 and IL-13 in BALF. In conclusion, regular/moderate aerobic training prior to allergic asthma induction reduced inflammation and remodeling, perhaps through increased IL-10 and IFN-γ in tandem with decreased Th2 cytokines.
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