Endothelial Transcytosis in Acute Lung Injury: Emerging Mechanisms and Therapeutic Approaches.

Acute Lung Injury (ALI) is characterized by widespread inflammation which in its severe form, Acute Respiratory Distress Syndrome (ARDS), leads to compromise in respiration causing hypoxemia and death in a substantial number of affected individuals. Loss of endothelial barrier integrity, pneumocyte necrosis, and circulating leukocyte recruitment into the injured lung are recognized mechanisms that contribute to the progression of ALI/ARDS. Additionally, damage to the pulmonary microvasculature by Gram-negative and positive bacteria or viruses (e.

PV1 in Caveolae Controls Lung Endothelial Permeability.

Caveolae are prominent plasmalemmal invaginations in endothelial cells, especially in the lung vasculature, which comprises a vast surface area. PV1 (plasmalemmal vesicle-associated protein-1), a 60-kD glycoprotein expressed in endothelial cells, is essential for generating spoke-like diaphragmatic structures that span the neck region of endothelial caveolae. However, their role in caveolae-mediated uptake and endothelial-barrier function is unknown.

Lung Endothelial Transcytosis.

Transcytosis of macromolecules through lung endothelial cells is the primary route of transport from the vascular compartment into the interstitial space. Endothelial transcytosis is mostly a caveolae-dependent process that combines receptor-mediated endocytosis, vesicle trafficking via actin-cytoskeletal remodeling, and SNARE protein directed vesicle fusion and exocytosis. Herein, we review the current literature on caveolae-mediated endocytosis, the role of actin cytoskeleton in caveolae stabilization at the plasma membrane, actin remodeling during vesicle trafficking, and exocytosis of caveolar vesicles.

Submaximal exercise cardiac output is increased by 4 weeks of sprint interval training in young healthy males with low initial Q̇-V̇O2: Importance of cardiac response phenotype.

Cardiovascular adaptations to exercise, particularly at the individual level, remain poorly understood. Previous group level research suggests the relationship between cardiac output and oxygen consumption ([Formula: see text]-[Formula: see text]) is unaffected by training as submaximal [Formula: see text] is unchanged. We recently identified substantial inter-individual variation in the exercise [Formula: see text]-[Formula: see text] relationship that was correlated to stroke volume (SV) as opposed to arterial oxygen content.

Contribution of central and peripheral adaptations to changes in maximal oxygen uptake following 4 weeks of sprint interval training.

The current study examined the contribution of central and peripheral adaptations to changes in maximal oxygen uptake (V̇O) following sprint interval training (SIT). Twenty-three males completed 4 weekly SIT sessions (8 × 20-s cycling bouts at ∼170% of work rate at V̇O, 10-s recovery) for 4 weeks. Following completion of training, the relationship between changes in V̇O and changes in central (cardiac output) and peripheral (arterial-mixed venous oxygen difference (a-vOdiff), muscle capillary density, oxidative capacity, fibre-type distribution) adaptations was determined in all participants using correlation analysis.

Systemic vascular dysfunction is associated with emphysema burden in mild COPD.

Background: Cardiovascular diseases play a major role in morbidity and mortality in the earlier stages of COPD. We hypothesized that systemic vascular dysfunction would be present even in patients who are currently considered at "low-risk" for negative cardiovascular outcomes, i.e.

Do interindividual differences in cardiac output during submaximal exercise explain differences in exercising muscle oxygenation and ratings of perceived exertion?

Considerable interindividual differences in the Q˙-V˙O2 relationship during exercise have been documented but implications for submaximal exercise tolerance have not been considered. We tested the hypothesis that these interindividual differences were associated with differences in exercising muscle deoxygenation and ratings of perceived exertion (RPE) across a range of submaximal exercise intensities. A total of 31 (21 ± 3 years) healthy recreationally active males performed an incremental exercise test to exhaustion 24 h following a resting muscle biopsy.

Oral -acetylcysteine and exercise tolerance in mild chronic obstructive pulmonary disease.

Heightened oxidative stress is implicated in the progressive impairment of skeletal muscle vascular and mitochondrial function in chronic obstructive pulmonary disease (COPD). Whether accumulation of reactive oxygen species contributes to exercise intolerance in the early stages of COPD is unknown. The purpose of the present study was to determine the effects of oral antioxidant treatment with -acetylcysteine (NAC) on respiratory, cardiovascular, and locomotor muscle function and exercise tolerance in patients with mild COPD.

Emphysema on Thoracic CT and Exercise Ventilatory Inefficiency in Mild-to-Moderate COPD.

There is growing evidence that emphysema on thoracic computed tomography (CT) is associated with poor exercise tolerance in COPD patients with only mild-to-moderate airflow obstruction. We hypothesized that an excessive ventilatory response to exercise (ventilatory inefficiency) would underlie these abnormalities. In a prospective study, 19 patients (FEV = 82 ± 13%, 12 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1) and 26 controls underwent an incremental exercise test.

Dietary nitrate supplementation and exercise tolerance in patients with heart failure with reduced ejection fraction.

Endothelial dysfunction and reduced nitric oxide (NO) signaling are key abnormalities leading to skeletal muscle oxygen delivery-utilization mismatch and poor physical capacity in patients with heart failure with reduced ejection fraction (HFrEF). Oral inorganic nitrate supplementation provides an exogenous source of NO that may enhance locomotor muscle function and oxygenation with consequent improvement in exercise tolerance in HFrEF. Thirteen patients (left ventricular ejection fraction ≤40%) were enrolled in a double-blind, randomized crossover study to receive concentrated nitrate-rich (nitrate) or nitrate-depleted (placebo) beetroot juice for 9 days.

A 56-Year-Old, Otherwise Healthy Woman Presenting With Light-headedness and Progressive Shortness of Breath.

A 56-year-old white woman was referred to the pulmonary clinic for evaluation of unexplained shortness of breath. She enjoyed good health until 3 months prior to this visit when she reported experiencing recurrent episodes of shortness of breath and oppressive retrosternal chest discomfort with radiation to the neck. Episodes lasting 5 to 10 min often occurred at rest and were inconsistently related to physical activity.

Does impaired O2 delivery during exercise accentuate central and peripheral fatigue in patients with coexistent COPD-CHF?

Impairment in oxygen (O2) delivery to the central nervous system ("brain") and skeletal locomotor muscle during exercise has been associated with central and peripheral neuromuscular fatigue in healthy humans. From a clinical perspective, impaired tissue O2 transport is a key pathophysiological mechanism shared by cardiopulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). In addition to arterial hypoxemic conditions in COPD, there is growing evidence that cerebral and muscle blood flow and oxygenation can be reduced during exercise in both isolated COPD and CHF.

Risperidone and the 5-HT2A receptor antagonist M100907 improve probabilistic reversal learning in BTBR T + tf/J mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with restricted interests and repetitive behaviors (RRBs). RRBs can severely limit daily living and be particularly stressful to family members. To date, there are limited options for treating this feature in ASD.

Differences in BTBR T+ tf/J and C57BL/6J mice on probabilistic reversal learning and stereotyped behaviors.

Autism spectrum disorders (ASD) represent a class of neurodevelopmental disorders characterized by impairments in social interaction, verbal and non-verbal communication, as well as restricted interests and repetitive behavior. This latter class of symptoms often includes features such as compulsive behaviors and resistance to change. The BTBR T+ tf/J mouse strain has been used as an animal model to investigate the social communication and restricted interest features in ASD.

A general organocatalyzed Michael-Michael cascade reaction generates functionalized cyclohexenes.

Although β-dicarbonyl compounds are regularly employed as Michael donors, intermediates arising from the Michael addition of unsaturated β-ketoesters to α,β-unsaturated aldehydes are susceptible to multiple subsequent reaction pathways. We designed cyclic unsaturated β-ketoester substrates that enabled the development of the first diphenyl prolinol silyl ether catalyzed Michael-Michael cascade reaction initiated by a β-dicarbonyl Michael donor to form cyclohexene products. The reaction conditions we developed for this Michael-Michael cascade reaction were also amenable to a variety of linear unsaturated β-ketoester substrates, including some of the same linear unsaturated β-ketoester substrates that were previously ineffective in Michael-Michael cascade reactions.