RESUMEN
Rationale: Immune dysregulation is a common feature of pulmonary arterial hypertension (PAH). Histone deacetylase (HDAC)-dependent transcriptional reprogramming epigenetically modulates immune homeostasis and is a novel disease-oriented approach in modern times. Objectives: To identify a novel functional link between HDAC and regulatory T cells (Tregs) in PAH, aiming to establish disease-modified biomarkers and therapeutic targets. Methods: Peripheral blood mononuclear cells were isolated from patients with idiopathic PAH (IPAH) and rodent models of pulmonary hypertension (PH): monocrotaline rats, Sugen5416-hypoxia rats, and Treg-depleted mice. HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) was used to examine the immune modulatory effects in vivo, ex vivo, and in vitro. Measurements and Main Results: Increased HDAC expression was associated with reduced Foxp3+ Tregs and increased PD-1 (programmed cell death-1) signaling in peripheral blood mononuclear cells from patients with IPAH. SAHA differentially modified a cluster of epigenetic-sensitive genes and induced Foxp3+ Treg conversion in IPAH T cells. Rodent models recapitulated these epigenetic aberrations and T-cell dysfunction. SAHA attenuated PH phenotypes and restored FOXP3 transcription and Tregs in PH rats; interestingly, the effects were more profound in female rats. Selective depletion of CD25+ Tregs in Sugen5416-hypoxia mice neutralized the effects of SAHA. Furthermore, SAHA inhibited endothelial cytokine/chemokine release upon stimulation and subsequent immune chemotaxis. Conclusions: Our results indicated HDAC aberration was associated with Foxp3+ Treg deficiency and demonstrated an epigenetic-mediated mechanism underlying immune dysfunction in PAH. Restoration of Foxp3+ Tregs by HDAC inhibitors is a promising approach to resolve pulmonary vascular pathology, highlighting the potential benefit of developing epigenetic therapies for PAH.
RESUMEN
BACKGROUND: Older Syrian refugees in Lebanon are a marginalized population with under-recognized health needs. The inclusivity of this population within the humanitarian response is poorly understood. This study aims to identify the unique needs of older Syrian refugees in the context of recent concurrent crises in Lebanon, and explore the extent to which they are being met and prioritized by local and international aid agencies. METHODS: We conducted in-depth interviews with a snowball sample of 26 stakeholders from 11 organizations operating in the health, nutrition, and water, sanitation, and hygiene sectors. Data analysis followed principles of thematic analysis. RESULTS: Concurrent political, economic, and public health crises in host country promoted income insecurity among older refugees and increased dependency on younger relatives, leading to food insecurity, neglect, and poor health outcomes, including the sequelae of untreated non-communicable diseases. Mental illness was perceived to be exacerbated by Covid-19 related challenges, including social isolation, uncertainty about the future, and additionally due to feelings of guilt related to economic dependence and fundamental exclusion from labor force participation. Despite their vulnerability, older refugees are overlooked by the humanitarian response, which may be related to a lack of data. Pervasive medication shortages in the setting of the economic collapse, as well as inaccessible physical environments and competing interests were all identified as major barriers to care. CONCLUSIONS: Older Syrian refugees in Lebanon experience dual vulnerability that is acutely exacerbated in the setting of concurrent crises. Sociopolitical, economic, and cultural barriers promote social exclusion and may confer an increased risk of income and food insecurity in this population, with significant implications for health. Humanitarian aid agencies operating in the context of fragmented, under-resourced health systems are currently unable to sufficiently address multi-faceted needs of this community. We recommend moving away from a donor-dependent model of aid by allocating resources toward strengthening inclusive national health systems that emphasize preventative care. We further call for age-disaggregation of routine data and normalization of data sharing among stakeholders in the academic and public health sectors in order to develop evidence-based initiatives that can meet the needs of this under-served community.