Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix-fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH4OH, creating the IPF-CM. Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of 'HIF1α signaling pathway' (KEGG, p < 0.0001), with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1. IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib.

Chewing versus Swallowing Ticagrelor to Accelerate Platelet Inhibition in Acute Coronary Syndrome - the CHEERS study. For The PLATIS (Platelets and Thrombosis in Sheba) Study Group.

It was the study objective to evaluate whether chewing a 180 mg loading dose of ticagrelor versus an equal dose of traditional oral administration, enhances inhibition of platelet aggregation 1 hour (h) after administering a ticagrelor loading dose in non-ST elevation myocardial infarction (NSTEMI) patients. Dual anti-platelet therapy represents standard care for treating NSTEMI patients. Ticagrelor is a direct acting P2Y12 inhibitor and, unlike clopidogrel and prasugrel, does not require metabolic activation. Fifty NSTEMI patients were randomised to receive either a chewing loading dose of 180 mg ticagrelor or an equal standard oral dose of ticagrelor. Platelet reactivity was evaluated by VerifyNow at baseline, 1 and 4 h post-loading dose. Results are reported in P2Y12 reaction units. Patients then continued to receive standard 90 mg oral ticagrelor twice daily. Baseline characteristics did not differ between the two groups. P2Y12 reaction units in the chewing group compared with the standard group at 0, 1 and 4 h after ticagrelor loading dose were: 245 vs 239 (p=0.59), 45 vs 130 (p=0.001) and 39 vs 60 (p=0.12), respectively, corresponding to a relative inhibition of platelet aggregation of 83 % vs only 47 % at 1 h (p< 0.001), and 84 % vs 77 % (p=0.59) at 4 h. Major adverse cardiac and cardiovascular events at 30 days were low (2 %), occurring in only one patient in the standard group. In conclusion, chewing a 180 mg ticagrelor loading dose is feasible and facilitates both faster and improved early inhibition of platelet aggregation in NSTEMI patients, compared with a standard oral-loading dose.