The resolution of acute inflammation induced by cyclic AMP is dependent on annexin A1

Annexin A1 (AnxA1) is a glucocorticoid-regulated protein known for its anti-inflammatory and pro-resolving effects. We have shown previously that the cAMP-enhancing compounds rolipram (ROL; a PDE4 inhibitor) and Bt2cAMP (a cAMP mimetic) drive caspase-dependent resolution of neutrophilic inflammation. In this follow-up study, we investigated whether AnxA1 could be involved in the pro-resolving properties of these compounds using a model of LPS-induced inflammation in BALB/c mice. The treatment with ROL or Bt2cAMP at the peak of inflammation shortened resolution intervals, improved resolution indices, and increased AnxA1 expression. In vitro studies showed that ROL and Bt2cAMP induced AnxA1 expression and phosphorylation, and this effect was prevented by PKA inhibitors, suggesting the involvement of PKA in ROL-induced AnxA1 expression. Akin to these in vitro findings, H89 prevented ROL- and Bt2cAMP-induced resolution of inflammation, and it was associated with decreased levels of intact AnxA1. Moreover, two different strategies to block the AnxA1 pathway (by using N-t-Boc-Met-Leu-Phe, a nonselective AnxA1 receptor antagonist, or by using an anti-AnxA1 neutralizing antiserum) prevented ROL- and Bt2cAMP-induced resolution and neutrophil apoptosis. Likewise, the ability of ROL or Bt2cAMP to induce neutrophil apoptosis was impaired in AnxA-knock-out mice. Finally, in in vitro settings, ROL and Bt2cAMP overrode the survival-inducing effect of LPS in human neutrophils in an AnxA1-dependent manner. Our results show that AnxA1 is at least one of the endogenous determinants mediating the pro-resolving properties of cAMP-elevating agents and cAMP-mimetic drug

Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis.

Nonphlogistic migration of macrophages contributes to the clearance of pathogens and apoptotic cells, a critical step for the resolution of inflammation and return to homeostasis. Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide of the renin-angiotensin system that acts through Mas receptor (MasR). Ang-(1-7) has recently emerged as a novel proresolving mediator, yet Ang-(1-7) resolution mechanisms are not fully determined. Herein, Ang-(1-7) stimulated migration of human and murine monocytes/macrophages in a MasR-, CCR2-, and MEK/ERK1/2-dependent manner. Pleural injection of Ang-(1-7) promoted nonphlogistic mononuclear cell influx alongside increased levels of CCL2, IL-10, and macrophage polarization toward a regulatory phenotype. Ang-(1-7) induction of CCL2 and mononuclear cell migration was also dependent on MasR and MEK/ERK. Of note, MasR was upregulated during the resolution phase of inflammation, and its pharmacological inhibition or genetic deficiency impaired mononuclear cell recruitment during self-resolving models of LPS pleurisy and E. coli peritonitis. Inhibition/absence of MasR was associated with reduced CCL2 levels, impaired phagocytosis of bacteria, efferocytosis, and delayed resolution of inflammation. In summary, we have uncovered a potentially novel proresolving feature of Ang-(1-7), namely the recruitment of mononuclear cells favoring efferocytosis, phagocytosis, and resolution of inflammation. Mechanistically, cell migration was dependent on MasR, CCR2, and the MEK/ERK pathway

The role of polymerization cycle and post-pressing time on tooth movement in complete dentures

This study analyzed the influence of polymerization cycle and post-pressing time on tooth movement in complete dentures. Forty maxillary complete dentures were fabricated and randomly assigned to 8 groups (n = 5); the polymerization cycle (conventional long cycle in water bath, fast cycle in boiling water, and by microwave energy) and the post-pressing time (immediate and 6 hours) were varied. Metal reference pins were placed on the incisal border of the central incisors (RI and LI), on the buccal cusp of the first premolars (RP and LP), and on the mesiobuccal cusp of the second molars (RM and LM). Two transverse and 2 anteroposterior distances were measured with a linear optical microscope (Olympus Optical Co., Tokyo, Japan) with an accuracy of .0005 mm, before and after processing the complete dentures. The data collected were submitted to analysis of variance (ANOVA) and the Tukey Test at a significance level of 5%. When Clássico, a conventional heat-polymerizable acrylic resin, was polymerized by microwave energy, tooth movement was statistically significant for 2 distances, with the highest value being observed for the 6-hour post-pressing time. Onda-Cryl microwave acrylic resin processed by microwave energy presented the lowest tooth movement for 2 distances, considering the 6-hour post-pressing time. QC-20 acrylic resin presented no statistically significant change considering both post-pressing times in each distance evaluated. Tooth movement showed an asymmetric behavior, so the mastering of the processing method is essential to the precise execution of all laboratory steps, irrespective of the polymerization cycle and post-pressing time used