Sex-specific lung diseases: effect of oestrogen on cultured cells and in animal models

Sex prevalence in lung disease suggests that sex-specific hormones may contribute to the pathogenesis and/or progression of at least some lung diseases, such as lung adenocarcinoma, lymphangioleiomyomatosis (LAM) and benign metastasising leiomyoma (BML). Oestrogen is an important hormone in normal lung development and in the pathogenesis of female predominant pulmonary diseases. In vivo and in vitro studies have facilitated our understanding of disease pathogenesis and discovery of potential therapeutic targets. Oestrogen promoted disease progression in cell and animal models of lung adenocarcinoma, LAM and BML. Specifically, oestrogen enhanced tumour growth and metastasis in animal models of these diseases. Furthermore, 17β-estradiol (E2), the most abundant form of oestrogen in humans, increased the size and proliferation of cultured cells of lung adenocarcinoma and LAM. Coupled with the known mechanisms of oestrogen metabolism and signalling, these model systems may provide insights into the diverse effects of oestrogen and other hormones on lung diseases. Anti-oestrogen treatments that target key events of oestrogen synthesis or signalling, such as aromatase activity, oestrogen receptors and signalling pathways, may offer additional opportunities for clinical trials

Anesthetic Efficacy of Dexmedetomidine versus Midazolam When Combined with Remifentanil for Percutaneous Transluminal Angioplasty in Patients with Peripheral Artery Disease

Anesthesia for percutaneous transluminal angioplasty (PTA) involves a high-risk population having a broad spectrum of pain character and intensity. This study delved the anesthetic efficacy of dexmedetomidine versus midazolam, when used with remifentanil. Seventy patients scheduled for femoropopliteal PTA were randomized into two groups receiving either intermittent midazolam boluses (0.03–0.05 mg/kg) (MR group) or dexmedetomidine 0.2–0.7 μg/kg/h after a loading dose of 1.0 μg/kg for 10 min (DR group), both with remifentanil. The primary endpoint was the patients’ satisfaction (1–5, 5; extremely satisfied). Secondary endpoints included postprocedural pain scores (0–10, 10; worst imaginable pain) and adverse events. The satisfaction level of patients was significantly greater in the DR group compared with the MR group (4.0 [3.0, 5.0] versus 4.0 [2.0, 5.0] p = 0.021). The number of patients having a postprocedural pain score of at least 3 was significantly greater in the MR group compared with the DR group (10 [29%] versus 2 [6%], p = 0.013). The number of patients with hypotensive episodes was higher in the DR group (5 [14.7%] versus 0, p = 0.025), which could all be restored with ephedrine. The use of dexmedetomidine in conjunction with remifentanil may be a safe option that provides excellent patient satisfaction while potentially attenuating postprocedural pain

Canagliflozin, an Inhibitor of the Na⁺-Coupled D-Glucose Cotransporter, SGLT2, Inhibits Astrocyte Swelling and Brain Swelling in Cerebral Ischemia

Brain swelling is a major cause of death and disability in ischemic stroke. Drugs of the gliflozin class, which target the Na+-coupled D-glucose cotransporter, SGLT2, are approved for type 2 diabetes mellitus (T2DM) and may be beneficial in other conditions, but data in cerebral ischemia are limited. We studied murine models of cerebral ischemia with middle cerebral artery occlusion/reperfusion (MCAo/R). Slc5a2/SGLT2 mRNA and protein were upregulated de novo in astrocytes. Live cell imaging of brain slices from mice following MCAo/R showed that astrocytes responded to modest increases in D-glucose by increasing intracellular Na+ and cell volume (cytotoxic edema), both of which were inhibited by the SGLT2 inhibitor, canagliflozin. The effect of canagliflozin was studied in three mouse models of stroke: non-diabetic and T2DM mice with a moderate ischemic insult (MCAo/R, 1/24 h) and non-diabetic mice with a severe ischemic insult (MCAo/R, 2/24 h). Canagliflozin reduced infarct volumes in models with moderate but not severe ischemic insults. However, canagliflozin significantly reduced hemispheric swelling and improved neurological function in all models tested. The ability of canagliflozin to reduce brain swelling regardless of an effect on infarct size has important translational implications, especially in large ischemic strokes

Brain Swelling versus Infarct Size: A Problematizing Review

In human stroke, brain swelling is an important predictor of neurological outcome and mortality, yet treatments to reduce or prevent brain swelling are extremely limited, due in part to an inadequate understanding of mechanisms. In preclinical studies on cerebroprotection in animal models of stroke, historically, the focus has been on reducing infarct size, and in most studies, a reduction in infarct size has been associated with a corresponding reduction in brain swelling. Unfortunately, such findings on brain swelling have little translational value for treating brain swelling in patients with stroke. This is because, in humans, brain swelling usually becomes evident, either symptomatically or radiologically, days after the infarct size has stabilized, requiring that the prevention or treatment of brain swelling target mechanism(s) that are independent of a reduction in infarct size. In this problematizing review, we highlight the often-neglected concept that brain edema and brain swelling are not simply secondary, correlative phenomena of stroke but distinct pathological entities with unique molecular and cellular mechanisms that are worthy of direct targeting. We outline the advances in approaches for the study of brain swelling that are independent of a reduction in infarct size. Although straightforward, the approaches reviewed in this study have important translational relevance for identifying novel treatment targets for post-ischemic brain swelling

Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke

Brain swelling causes morbidity and mortality in various brain injuries and diseases but lacks effective treatments. Brain swelling is linked to the influx of water into perivascular astrocytes through channels called aquaporins. Water accumulation in astrocytes increases their volume, which contributes to brain swelling. Using a mouse model of severe ischemic stroke, we identified a potentially targetable mechanism that promoted the cell surface localization of aquaporin 4 (AQP4) in perivascular astrocytic endfeet, which completely ensheathe the brain\u27s capillaries. Cerebral ischemia increased the abundance of the heteromeric cation channel SUR1-TRPM4 and of the Na/Ca exchanger NCX1 in the endfeet of perivascular astrocytes. The influx of Na through SUR1-TRPM4 induced Ca transport into cells through NCX1 operating in reverse mode, thus raising the intra-endfoot concentration of Ca. This increase in Ca stimulated calmodulin-dependent translocation of AQP4 to the plasma membrane and water influx, which led to cellular edema and brain swelling. Pharmacological inhibition or astrocyte-specific deletion of SUR1-TRPM4 or NCX1 reduced brain swelling and improved neurological function in mice to a similar extent as an AQP4 inhibitor and was independent of infarct size. Thus, channels in astrocyte endfeet could be targeted to reduce postischemic brain swelling in stroke patients