Budesonide, Aclidinium and Formoterol in combination limit inflammaging processes in bronchial epithelial cells exposed to cigarette smoke.

Inflammation and cellular senescence (also called inflammaging) are involved in the pathogenesis of premature lung aging, a key driver of chronic obstructive pulmonary disease (COPD). Downregulation of histone deacetylases and FoxO3 expression, activation of the ERK 1/2 pathway and IL-8 increase are hallmarks of lung inflammaging. The effects of Budesonide (BUD), Aclidinium (ACL) and Formoterol (FO) on lung inflammaging are unknown. This study was aimed to assess the effects of BUD, ACL and FO in bronchial epithelial cells exposed to cigarette smoke extract (CSE) by evaluating: a) Expression of TLR4 and survivin and LPS binding by flow cytometry; b) expression of HDAC2, HDAC3, SIRT1 and FoxO3 and activation of the ERK 1/2 pathway by western blot; c) IL-8 mRNA levels and release by Real Time-PCR and ELISA, respectively. Reported results show that CSE increased TLR4 and survivin, LPS binding, ERK 1/2 activation, IL-8 release and mRNA levels but decreased SIRT1, HDAC2, HDAC3 and FoxO3 nuclear expression. Combined therapy with BUD, ACL and FO counteracted the effects of CSE on LPS binding, FoxO3 nuclear expression, ERK 1/2 activation, survivin and IL-8 release and mRNA levels. These findings suggest a new role of combination therapy with BUD, ACL and FO in counteracting inflammaging processes induced by cigarette smoke exposure.

Ceftaroline modulates the innate immune and host defense responses of immunocompetent cells exposed to cigarette smoke.

BACKGROUND: Cigarette smoke, the principal risk factor for chronic obstructive pulmonary disease (COPD), negatively influences the effectiveness of the immune system's response to a pathogen. The antibiotic ceftaroline exerts immune-modulatory effects in bronchial epithelial cells exposed to cigarette smoke. AIMS AND METHODS: The present study aims to assess the effects of ceftaroline on TLR2 and TLR4 expression, LPS binding and TNF-α and human beta defensin (HBD2) release in an undifferentiated and PMA-differentiated human monocyte cell line (THP-1) exposed or not to cigarette smoke extracts (CSE). TLR2, TLR4, and LPS binding were assessed by flow cytometry, TNF-α and HBD2 release were evaluated by ELISA. RESULTS: The constitutive expression of TLR2 and TLR4 and LPS binding were higher in differentiated compared to undifferentiated THP-1 cells. In undifferentiated THP-1 cells, CSE increased TLR2 and TLR4 protein levels, LPS binding and TNF-α release and reduced HBD2 release and ceftaroline counteracted all these effects. In differentiated THP-1, CSE did not significantly affect TLR2 and TLR4 expression and LPS binding but reduced HBD2 release and increased TNF-α release. Ceftaroline counteracted the effects of CSE on HBD2 release in differentiated THP-1. CONCLUSION: Ceftaroline counteracts the effect of CSE in immune cells by increasing the effectiveness of the innate immune system. This effect may also assist in reducing pathogen activity and recurrent exacerbations in COPD patients.

Umbilical flow in the normal and pre-eclamptic placenta. A study in vitro.

In order to develop a simple in vitro method for assessing adequacy of placental perfusion, umbilical flow was measured in placentae from 10 normal control women and from 10 women with pre-eclampsia, by infusing through the umbilical arteries a heparinized 0.9% saline solution. The average induced umbilical flow in placentae from uneventful pregnancies was 276 +/- 16 SE ml/min compared with 163 +/- 12 ml/min (p less than 0.001) in the pre-eclamptic group. In angiographic studies, 79 +/- 2 SE% of the cotyledons from the normal series, and only 56 +/- 3% (p less than 0.001) from the pre-eclamptic series were functional. Additionally, gross and histological examination revealed three distinct types of cotyledon. Placental areas that blanched following saline infusion showed no blood in the collapsed villi or in the intervillous space; areas distinguished by a ruddy appearance following perfusion showed blood trapped in the villi and in the intervillous space; in a third area, the findings were mixed. When compared with placental zones identified by perfusion with 5% Hypaque solution, these three anatomical regions corresponded to normal, reduced, or absent flow (blanched, intermediate, or ruddy regions, respectively). We conclude that under the conditions of this in vitro study, pre-eclamptic placentae had a greater proportion of umbilical perfusion deficits than had normal placentae.