Atherosclerosis develops near branches and bends of arteries that are exposed to low shear stress (mechanical drag). These sites are characterized by excessive endothelial cell (EC) proliferation and ...inflammation that promote lesion initiation. The transcription factor HIF1α (hypoxia-inducible factor 1α) is canonically activated by hypoxia and has a role in plaque neovascularization. We studied the influence of shear stress on HIF1α activation and the contribution of this noncanonical pathway to lesion initiation.
Quantitative polymerase chain reaction and en face staining revealed that HIF1α was expressed preferentially at low shear stress regions of porcine and murine arteries. Low shear stress induced HIF1α in cultured EC in the presence of atmospheric oxygen. The mechanism involves the transcription factor nuclear factor-κB that induced HIF1α transcripts and induction of the deubiquitinating enzyme Cezanne that stabilized HIF1α protein. Gene silencing revealed that HIF1α enhanced proliferation and inflammatory activation in EC exposed to low shear stress via induction of glycolysis enzymes. We validated this observation by imposing low shear stress in murine carotid arteries (partial ligation) that upregulated the expression of HIF1α, glycolysis enzymes, and inflammatory genes and enhanced EC proliferation. EC-specific genetic deletion of HIF1α in hypercholesterolemic apolipoprotein E-defecient mice reduced inflammation and endothelial proliferation in partially ligated arteries, indicating that HIF1α drives inflammation and vascular dysfunction at low shear stress regions.
Mechanical low shear stress activates HIF1α at atheroprone regions of arteries via nuclear factor-κB and Cezanne. HIF1α promotes atherosclerosis initiation at these sites by inducing excessive EC proliferation and inflammation via the induction of glycolysis enzymes.
To determine whether global reduction of CD68 (cluster of differentiation) macrophages impacts the development of experimental pulmonary arterial hypertension (PAH) and whether this reduction affects ...the balance of pro- and anti-inflammatory macrophages within the lung. Additionally, to determine whether there is evidence of an altered macrophage polarization in patients with PAH. Approach and Results: Macrophage reduction was induced in mice via doxycycline-induced CD68-driven cytotoxic diphtheria toxin A chain expression (macrophage low MacLow mice). Chimeric mice were generated using bone marrow transplant. Mice were phenotyped for PAH by echocardiography and closed chest cardiac catheterization. Murine macrophage phenotyping was performed on lungs, bone marrow-derived macrophages, and alveolar macrophages using immunohistochemical and flow cytometry. Monocyte-derived macrophages were isolated from PAH patients and healthy volunteers and polarization capacity assessed morphologically and by flow cytometry. After 6 weeks of macrophage depletion, male but not female MacLow mice developed PAH. Chimeric mice demonstrated a requirement for both MacLow bone marrow and MacLow recipient mice to cause PAH. Immunohistochemical analysis of lung sections demonstrated imbalance in M1/M2 ratio in male MacLow mice only, suggesting that this imbalance may drive the PAH phenotype. M1/M2 imbalance was also seen in male MacLow bone marrow-derived macrophages and PAH patient monocyte-derived macrophages following stimulation with doxycycline and IL (interleukin)-4, respectively. Furthermore, MacLow-derived alveolar macrophages showed characteristic differences in terms of their polarization and expression of diphtheria toxin A chain following stimulation with doxycycline.
These data further highlight a sex imbalance in PAH and further implicate immune cells into this paradigm. Targeting imbalance of macrophage population may offer a future therapeutic option.
•Observed slight symptoms of simulator sickness after immersion in the virtual environment.•Postural instability was greater after immersion, but may have been related to fatigue.•Consider longer ...acclimation period for treadmills coupled with virtual reality.•Moderate activity in this virtual environment did not affect ability to successfully complete tasks.
Virtual environments are a valuable rehabilitation tool that can be used to address unique patient-specific goals; however simulator sickness can cause feelings of discomfort and unwanted side effects that limit the effectiveness of treatment. The purpose of this research was to assess simulator-induced sickness (SIS) symptoms and postural stability before and after 45 min of immersion in a virtual environment with a treadmill-motion base and curved display.
Thirty able-bodied Canadian Armed Forces members participated in this study. Symptoms of SIS were evaluated using the Simulator Sickness Questionnaire and postural stability was quantified using centre of pressure data during quiet stance. SIS symptoms and postural stability were evaluated three times throughout the session – at the start of the session, after 15 min, and after 45 min. Participants reported mild simulator sickness symptoms, including eyestrain, headache, difficulty focusing, and dizziness after immersion in the virtual environment, which was below the acceptable level. Postural instability was greater after 45 min in the virtual environment, but did not affect participant’s ability to successfully complete the session. The data reported in this paper provide useful baseline information of a healthy military population for clinical assessments and future studies using a virtual environment with a treadmill-motion base and large curved display.
Pulmonary hypertension (PH) commonly affects patients with systemic sclerosis (SSc) and is associated with significant morbidity and increased mortality. PH is a heterogenous condition and several ...different forms can be associated with SSc, including pulmonary arterial hypertension (PAH) resulting from a pulmonary arterial vasculopathy, PH due to left heart disease and PH due to interstitial lung disease. The incidence of pulmonary veno-occlusive disease is also increased. Accurate and early diagnosis to allow optimal treatment is, therefore, essential. Recent changes to diagnostic haemodynamic criteria at the 6th World Symposium on Pulmonary Hypertension have resulted in therapeutic uncertainty regarding patients with borderline pulmonary haemodynamics. Furthermore, the optimal pulmonary vascular resistance threshold for diagnosing PAH and the role of exercise in identifying early disease require further elucidation. In this article we review the epidemiology, diagnosis, outcomes and treatment of the spectrum of pulmonary vascular phenotypes associated with SSc.
Summary There is an increasing body of evidence suggesting that altered vascular permeability may be an important component of the pathogenesis of acute mountain sickness (AMS). Vascular endothelial ...growth factor (VEGF) is a potent permeability factor subject to hypoxic regulation but its role in the pathogenesis of AMS is yet to be defined. We examined the relationship between plasma VEGF and AMS on ascent to high altitude and subsequent acclimatisation. Thirty-eight healthy lowlanders (median age 21, range 18–31) flew to La Paz, Bolivia (3650 m) on the Apex 2 research expedition. After 4–5 days acclimatisation, they ascended by vehicle over 90 min to the Chacaltaya laboratory (5200 m). We measured plasma VEGF in venous blood at sea level and at 6 h and 3 and 7 days at 5200 m. AMS was scored using the Lake Louise consensus system. Using serial measurement of plasma VEGF at 5200 m, following partial acclimatisation at 3650 m, we demonstrated a highly significant change in VEGF levels ( P <0.0005) with a rise in VEGF in approximately 80% of subjects by day 7 at 5200 m. We found no evidence of an association between AMS and change in VEGF levels on ascent to either 3650 or 5200 m. We provide novel data of change in plasma VEGF levels during acclimatisation to high altitude, but our results do not support the hypothesis that circulating unbound VEGF is an important component of the pathogenesis of AMS.
A rapid, quantitative serum S100A8/A9 (calprotectin) lateral flow test in combination with clinical status predicted outcomes in people hospitalised with COVID-19 and associated with a patient ...cluster driven by markers of neutrophil activation https://bit.ly/48e1BIv.A rapid, quantitative serum S100A8/A9 (calprotectin) lateral flow test in combination with clinical status predicted outcomes in people hospitalised with COVID-19 and associated with a patient cluster driven by markers of neutrophil activation https://bit.ly/48e1BIv.
Pulmonary hypertension (PH) is a life-shortening condition characterised by episodes of decompensation precipitated by factors such as disease progression, arrhythmias and sepsis. Surgery and ...pregnancy also place additional strain on the right ventricle. Data on critical care management in patients with pre-existing PH are scarce. We conducted a retrospective observational study of a large cohort of patients admitted to the critical care unit of a national referral centre between 2000-2017 to establish acute mortality, evaluate predictors of in-hospital mortality and establish longer term outcomes in survivors to hospital discharge. 242 critical care admissions involving 206 patients were identified. Hospital survival was 59.3%, 94% and 92% for patients admitted for medical, surgical or obstetric reasons, respectively. Medical patients had more severe physiological and laboratory perturbations than patients admitted following surgical or obstetric interventions. Higher APACHE II (Acute Physiology and Chronic Health Evaluation) score, age and lactate, and lower oxygen saturation measure by pulse oximetry/inspiratory oxygen fraction (
/
) ratio, platelet count and sodium level were identified as independent predictors of hospital mortality. An exploratory risk score, OPALS (oxygen (
/
) ≤185; platelets ≤196×10
·L
; age ≥37.5 years; lactate ≥2.45 mmol·L
; sodium ≤130.5 mmol·L
), identified medical patients at increasing risk of hospital mortality. One (11%) out of nine patients who were invasively ventilated for medical decompensation and 50% of patients receiving renal replacement therapy left hospital alive. There was no significant difference in exercise capacity or functional class between follow-up and pre-admission in patients who survived to discharge. These data have clinical utility in guiding critical care management of patients with known PH. The exploratory OPALS score requires validation.
Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs ...have emerged as critical mediators of lung damage, inflammation and thrombosis in coronavirus disease 2019 (COVID-19) and other diseases, but there are no therapeutics to prevent or reduce NETs that are available to patients.
Neutrophils were isolated from healthy volunteers (n=9) and hospitalised patients with COVID-19 at the acute stage (n=39) and again at 3-4 months post-acute sampling (n=7). NETosis was measured by SYTOX green assays.
Here, we show that neutrophils isolated from hospitalised patients with COVID-19 produce significantly more NETs in response to lipopolysaccharide (LPS) compared to cells from healthy control subjects. A subset of patients was captured at follow-up clinics (3-4 months post-acute sampling), and while LPS-induced NET formation is significantly lower at this time point, it remains elevated compared to healthy controls. LPS- and phorbol myristate acetate (PMA)-induced NETs were significantly inhibited by the protein kinase C (PKC) inhibitor ruboxistaurin. Ruboxistaurin-mediated inhibition of NETs in healthy neutrophils reduces NET-induced epithelial cell death.
Our findings suggest ruboxistaurin could reduce proinflammatory and tissue-damaging consequences of neutrophils during disease, and since it has completed phase III trials for other indications without safety concerns, it is a promising and novel therapeutic strategy for COVID-19.
Pulmonary hypertension (PH) in patients with chronic lung disease (CLD) predicts reduced functional status, clinical worsening and increased mortality, with patients with severe PH-CLD (≥35 mmHg) ...having a significantly worse prognosis than mild to moderate PH-CLD (21-34 mmHg). The aim of this cross-sectional study was to assess the association between computed tomography (CT)-derived quantitative pulmonary vessel volume, PH severity and disease aetiology in CLD.
Treatment-naïve patients with CLD who underwent CT pulmonary angiography, lung function testing and right heart catheterisation were identified from the ASPIRE registry between October 2012 and July 2018. Quantitative assessments of total pulmonary vessel and small pulmonary vessel volume were performed.
90 patients had PH-CLD including 44 associated with COPD/emphysema and 46 with interstitial lung disease (ILD). Patients with severe PH-CLD (n=40) had lower small pulmonary vessel volume compared to patients with mild to moderate PH-CLD (n=50). Patients with PH-ILD had significantly reduced small pulmonary blood vessel volume, compared to PH-COPD/emphysema. Higher mortality was identified in patients with lower small pulmonary vessel volume.
Patients with severe PH-CLD, regardless of aetiology, have lower small pulmonary vessel volume compared to patients with mild-moderate PH-CLD, and this is associated with a higher mortality. Whether pulmonary vessel changes quantified by CT are a marker of remodelling of the distal pulmonary vasculature requires further study.
Many inflammatory diseases are characterised by persistent and inappropriate neutrophil activation, systemic or localised hypoxia, and bacterial colonisation. Hypoxia represents an important ...regulator of inflammatory responses because it inhibits neutrophil apoptosis, a process central to the timely resolution of inflammation. Progress in understanding how cells respond to hypoxia has led to the identification of hypoxia-inducible transcription factors (HIFs) and their hydroxylation by the prolyl hydroxylase enzymes. There is now a significant body of data to support a critical role for this HIF pathway in regulating neutrophil function. Moreover, manipulations of specific components of this pathway have very divergent effects on myeloid cell function. In this review, we will discuss the role individual members of the HIF pathway play in regulating key neutrophil functions and the implications this has for the development of effective therapeutic strategies that selectively target inappropriate neutrophil persistence while maintaining a fully competent immune response.
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