The Essential Role of PGF2α/PTGFR in Molding Endometrial Breakdown and Vascular Dynamics, Regulated by HIF-1α in a Mouse Menstrual-like Model.

In women of childbearing age, extensive decidualization, shedding and remodeling of the endometrium during the menstrual cycle are fundamental for successful pregnancy. The role of prostaglandins (PGs) in menstruation has long been proposed in humans, and the rate-limiting enzyme cyclooxygenase was shown to play a key role in endometrial breakdown and shedding in a mouse menstrual-like model in our previous study. However, the specific types of PGs involved and their respective roles remain unclear. Therefore, our objective was to investigate the mechanism through which PGs regulate endometrial disintegration. In this study, the microscopy was observed by HE; the protein levels of prostaglandins E1 (PGE1), prostaglandins E2 (PGE2), prostaglandin F2α (PGF2α) and Prostaglandin I2 (PGI2) were detected by ELISA; the mRNA level of Pfgfr2, Vascular Endothelial Growth Factor(Vegf), Angiostatin and Hypoxia inducible factor-1α (Hif1α) were examined by real-time PCR; PTGFR Receptor (PTGFR), VEGF, Angiostatin and HIF-1α protein levels were investigated by western blotting; the locations of protein were observed by Immunohistochemistry; HIF-1α binding PTGFR promoter was detected by Chromatin Immunoprecipitation (ChIP) and real-time PCR. We found that the concentrations of PGE1, PGE2, and PGF2α all increased significantly during this process. Furthermore, Ptgfr mRNA increased soon after Progesterone (P4) withdrawal, and PTGFR protein levels increased significantly during abundant endometrial breakdown and shedding processes. PTGFR inhibitors AL8810 significantly suppressed endometrial breakdown and shedding, promoted Angiostatin expression, and reduced VEGF-A expressions and vascular permeability. And HIF-1α and PTGFR were mainly located in the luminal/gland epithelium, vascular endothelium, and pre-decidual zone. Interestingly, HIF-1α directly bound to Ptgfr promoter. Moreover, a HIF-1α inhibitor 2-methoxyestradiol (2ME) significantly reduced PTGFR expression and suppressed endometrial breakdown which was in accord with PTGFR inhibitor's effect. Similar changes occurred in human stromal cells relevant to menstruation in vitro. Our study provides evidence that PGF2α/PTGFR plays a vital role in endometrial breakdown via vascular changes that are regulated by HIF-1α during menstruation.

Cardiogenic Pulmonary Edema in Emergency Medicine.

Cardiogenic pulmonary edema (CPE) is characterized by the development of acute respiratory failure associated with the accumulation of fluid in the lung's alveolar spaces due to an elevated cardiac filling pressure. All cardiac diseases, characterized by an increasing pressure in the left side of the heart, can cause CPE. High capillary pressure for an extended period can also cause barrier disruption, which implies increased permeability and fluid transfer into the alveoli, leading to edema and atelectasis. The breakdown of the alveolar-epithelial barrier is a consequence of multiple factors that include dysregulated inflammation, intense leukocyte infiltration, activation of procoagulant processes, cell death, and mechanical stretch. Reactive oxygen and nitrogen species (RONS) can modify or damage ion channels, such as epithelial sodium channels, which alters fluid balance. Some studies claim that these patients may have higher levels of surfactant protein B in the bloodstream. The correct approach to patients with CPE should include a detailed medical history and a physical examination to evaluate signs and symptoms of CPE as well as potential causes. Second-level diagnostic tests, such as pulmonary ultrasound, natriuretic peptide level, chest radiograph, and echocardiogram, should occur in the meantime. The identification of the specific CPE phenotype is essential to set the most appropriate therapy for these patients. Non-invasive ventilation (NIV) should be considered early in the treatment of this disease. Diuretics and vasodilators are used for pulmonary congestion. Hypoperfusion requires treatment with inotropes and occasionally vasopressors. Patients with persistent symptoms and diuretic resistance might benefit from additional approaches (i.e., beta-agonists and pentoxifylline). This paper reviews the pathophysiology, clinical presentation, and management of CPE.

Cytokine-Mediated Degradation of the Transcription Factor ERG Impacts the Pulmonary Vascular Response to Systemic Inflammatory Challenge.

BACKGROUND: During infectious diseases, proinflammatory cytokines transiently destabilize interactions between adjacent vascular endothelial cells (ECs) to facilitate the passage of immune molecules and cells into tissues. However, in the lung, the resulting vascular hyperpermeability can lead to organ dysfunction. Previous work identified the transcription factor ERG (erythroblast transformation-specific-related gene) as a master regulator of endothelial homeostasis. Here we investigate whether the sensitivity of pulmonary blood vessels to cytokine-induced destabilization is due to organotypic mechanisms affecting the ability of endothelial ERG to protect lung ECs from inflammatory injury. METHODS: Cytokine-dependent ubiquitination and proteasomal degradation of ERG were analyzed in cultured HUVECs (human umbilical vein ECs). Systemic administration of TNFα (tumor necrosis factor alpha) or the bacterial cell wall component lipopolysaccharide was used to cause a widespread inflammatory challenge in mice; ERG protein levels were assessed by immunoprecipitation, immunoblot, and immunofluorescence. Murine Erg deletion was genetically induced in ECs (Ergfl/fl;Cdh5[PAC]-CreERT2), and multiple organs were analyzed by histology, immunostaining, and electron microscopy. RESULTS: In vitro, TNFα promoted the ubiquitination and degradation of ERG in HUVECs, which was blocked by the proteasomal inhibitor MG132. In vivo, systemic administration of TNFα or lipopolysaccharide resulted in a rapid and substantial degradation of ERG within lung ECs but not ECs of the retina, heart, liver, or kidney. Pulmonary ERG was also downregulated in a murine model of influenza infection. Ergfl/fl;Cdh5(PAC)-CreERT2 mice spontaneously recapitulated aspects of inflammatory challenges, including lung-predominant vascular hyperpermeability, immune cell recruitment, and fibrosis. These phenotypes were associated with a lung-specific decrease in the expression of Tek-a gene target of ERG previously implicated in maintaining pulmonary vascular stability during inflammation. CONCLUSIONS: Collectively, our data highlight a unique role for ERG in pulmonary vascular function. We propose that cytokine-induced ERG degradation and subsequent transcriptional changes in lung ECs play critical roles in the destabilization of pulmonary blood vessels during infectious diseases.

Expression and role of deleted in malignant brain tumor protein 1 in acute respiratory distress syndrome rats induced by sepsis / 中华危重病急救医学

Objective:To observe the expression of deleted in malignant brain tumor protein 1 (DMBT1) in rat acute respiratory distress syndrome (ARDS) model induced by sepsis and its relationship with ARDS related biomarkers.Methods:Forty-eight healthy male rats were randomly divided into sham operation group (Sham group) and ARDS model group, and the rats in each group were further divided into three subgroups at 6, 12 and 24 hours after operation, with 8 rats in each subgroup. The rats in the Sham group were exposed to the cecum only, and sepsis induced ARDS model was reproduced by cecal ligation and puncture (CLP) in the ARDS model group. The general performance was observed at 6, 12, 24 hours after operation. Abdominal aortic blood of rats was collected, and the levels of DMBT1, surfactant-associated protein D (SP-D), vascular endothelial growth factor (VEGF), interleukins (IL-6, IL-10) in serum were determined by enzyme-linked immunosorbent assay (ELISA). The lung tissues were collected, and the lung wet/dry weight (W/D) ratio was determined. The lung tissue pathological changes were observed under light microscope after hematoxylin-eosin (HE) staining, and the lung tissue injury score was evaluated. The expression of DMBT1 protein in lung tissue was determined by Western blotting. The relationship between the serum DMBT1 and SP-D, VEGF, IL-6, IL-10, lung tissue injury score were analyzed by Pearson correlation analysis.Results:Rats in the ARDS model group showed obvious pathological manifestations after operation. The alveolar structure destruction, inflammatory cell infiltration, and alveolar hemorrhage were observed under microscope. Compared with the Sham group, the lung tissue injury score and the lung W/D ratio at 12 hours after operation in the ARDS model group were significantly increased (lung tissue injury score: 3.35±0.13 vs. 1.16±0.07, lung W/D ratio: 5.36±0.44 vs. 4.38±0.35, both P < 0.05), and pulmonary edema was present, which suggested that the ARDS model caused by CLP was successfully reproduced. The results of ELISA and Western blotting showed that the levels of serum DMBT1, SP-D, VEGF and IL-6 in the ARDS model group increased gradually with time, while the level of IL-10 increased first and then decreased. Compared with the Sham group, the levels of DMBT1 in serum and the expressions of DMBT1 protein in lung tissue in the ARDS model group were significantly increased from 6 hours after operation [serum (ng/L) : 231.96±19.17 vs. 187.44±10.19, lung tissue (DMBT1/β-actin): 2.05±0.19 vs. 0.93±0.25, both P < 0.05], and the levels of SP-D, VEGF, IL-6 and IL-10 in serum were significantly increased from 12 hours after operation [SP-D (ng/L): 73.35±8.05 vs. 43.28±5.77, VEGF (ng/L): 89.85±8.47 vs. 43.19±5.11, IL-6 (ng/L): 36.01±2.48 vs. 17.49±1.77, IL-10 (ng/L): 84.55±8.41 vs. 39.83±5.02, all P < 0.05]. Pearson correlation analysis showed that serum DMBT1 was positively correlated with serum SP-D, VEGF, IL-6, IL-10 and lung injury score at 12 hours and 24 hours in the ARDS model group (12 hours: r values were 0.946, 0.942, 0.931, 0.936, 0.748, respectively; 24 hours: r values were 0.892, 0.945, 0.951, 0.918, 0.973, respectively; all P < 0.05). Conclusion:DMBT1 is a novel early biomarker of ARDS by affecting alveolar epithelial cell, alveolar capillary permeability and inflammatory response.

Macromolecules in polysorbate 80 for injection: an important cause of anaphylactoid reactions.

Polysorbate 80 for injection (TW80) is a common excipient used for injection whose macromolecular impurities, including those that cause anaphylactoid reactions, are frequently ignored. The main aim of this study was to prove that the macromolecular impurities in the excipient are an important cause of anaphylactoid reactions. Component A (containing macromolecules > 100 kDa), Component B (containing macromolecules from 10 to 100 kDa), and Component C (containing substances < 10 kDa) were prepaired from the original TW80 using ultrafilters. The original TW80 contained numerous substances with molecular weights > 10kD. The original TW80 and Components A and B caused strong anaphylactoid reactions in both guinea pigs and rabbits by intravenous administration. Moreover, the original TW80 and Components A and B even caused strong passive cutaneous anaphylactoid (PCA) reactions and pulmonary capillary permeability. The PCA reaction and increased permeability were partly prevented by cromolyn sodium. Additionally, the original TW80 and Components A and B caused vasodilation and severe hemolysis in vitro. The anaphylactoid reactions were associated with histamine release but not with mast cell degranulation. Nevertheless, Component C almost caused no anaphylactoid reactions or hemolysis and was weaker in the few reactions that ocurred. Taken together, these results suggest that macromolecular substances are one of the main risk factors responsible for anaphylactoid reactions and hemolysis caused by TW80.

Fast versus slow infusion of 20% albumin: a randomized controlled cross-over trial in volunteers.

BACKGROUND: We investigated whether plasma volume (PV) expansion of 20% albumin is larger when the fluid is administered rapidly compared with a slow infusion. METHODS: In this open-labeled randomized interventional controlled trial, 12 volunteers (mean age, 28 years) received 3 mL/kg of 20% albumin (approximately 225 mL) over 30 min (fast) and 120 min (slow) in a cross-over fashion. Blood hemoglobin and plasma albumin were measured on 15 occasions during 6 h to estimate the PV expansion and the capillary leakage of albumin and fluid. RESULTS: The largest PV expansion was 16.1% ± 6.5% (mean ± SD) for fast infusion and 12.8% ± 4.0% for slow infusion (p = 0.52). The median area under the curve for the PV expansion was 69% larger for the fast infusion during the first 2 h (p = 0.034), but was then similar for both infusions. The half-life of the PV expansion did not differ significantly (median, 5.6 h versus 5.4 h, p = 0.345), whereas the intravascular half-life of the excess albumin was 8.0 h for fast infusion and 6.3 h for slow infusion (p = 0.028). The measured urine output was almost three times larger than the infused volume. The plasma concentration of atrial natriuretic peptide (MR-proANP) accelerated the capillary leakage of albumin and the urine flow. CONCLUSIONS: The intravascular persistence of albumin was longer, but the fluid kinetics was the same, when 20% albumin was infused over 30 min compared with 120 min. We found no disadvantages of administering the albumin at the higher rate. Trial registration EU Clinical Trials Register, EudraCT2017-003687-12, registered September 22, 2017, https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-003687-12/SE.

Kinetics of 5% and 20% albumin: A controlled crossover trial in volunteers.

BACKGROUND: Albumin for intravenous infusion is marketed in two concentrations, 20% and 5%, but how they compare with regard to plasma volume expansion over time is unclear. METHODS: In a prospective crossover study, 12 volunteers received 3 ml kg-1 of 20% albumin and, on another occasion, 12 ml kg-1 of 5% albumin over 30 min. Hence, equivalent amounts of albumin were given. Blood was collected on 15 occasions over 6 h. Mass balance and volume kinetics were used to estimate the plasma volume expansion and the capillary leakage of albumin and fluid based on measurements of blood hemoglobin, plasma albumin, and the colloid osmotic pressure. RESULTS: The greatest plasma volume expansion was 16.0 ± 6.4% (mean ± SD) with 20% albumin and 19.0 ± 5.2% with 5% albumin (p < .03). The volume expansion with 20% albumin corresponded to twice the infused volume. One third of the 5% albumin volume quickly leaked out of the plasma, probably because of the higher colloid osmotic pressure of the volunteer plasma (mean, 24.5 mmHg) than the albumin solution (19.1 mmHg). At 6 h, the capillary leakage amounted to 42 ± 15% and 47 ± 11% of the administered albumin with the 20% and 5% preparations, respectively (p = .28). The corresponding urine outputs were 547 (316-780) ml and 687 (626-1080) ml (median and interquartile range; p = .24). CONCLUSION: The most important difference between the fluids was a dehydrating effect of 20% albumin when the same albumin mass was administered.

Early passage of Toxoplasma gondii across the blood-brain barrier.

The blood-brain barrier (BBB) efficiently protects the central nervous system (CNS) from infectious insults. Yet, the apicomplexan parasite Toxoplasma gondii has a remarkable capability to establish latent cerebral infection in humans and other vertebrates. In addition to the proposed mechanisms for access to the brain parenchyma, recent findings highlight a paramount role played by the BBB in restricting parasite passage and minimizing parasite loads in the brain. Consistent with clinically asymptomatic primary infections in humans, mounting evidence indicates that the original colonization of the brain by T. gondii encompasses previously unappreciated, nondisruptive translocation processes that precede the onset of parasite-limiting immune responses.

Elevated admission C-reactive protein to albumin ratios are associated with disease severity and respiratory complications in adults with imported falciparum malaria.

BACKGROUND: In imported falciparum malaria, systemic inflammation with increased capillary permeability can cause life-threatening complications, such as acute pulmonary edema (APO) or adult respiratory distress syndrome (ARDS). This observational study assessed the association of the admission serum albumin level (ALB) and C-reactive protein to albumin ratio (CRP/ALB) with disease severity and these respiratory complications. METHODS: All adult cases hospitalized during 2001-2015 in the Charité University Hospital, Berlin, with ALB and CRP values measured upon admission, were retrospectively analysed. RESULTS: Seventy-six patients were enrolled (26 female, median age: 37 y), 60 with uncomplicated malaria and 16 with severe malaria (SM). SM was associated with lower ALB (p<0.0001) and higher CRP/ALB (p<0.0001) values; the areas under the receiver operator curves (AUROCs) were 0.85 (95% CI 0.74 to 0.96) for ALB and 0.88 (95% CI 0.80 to 0.97) for CRP/ALB. Radiologic changes consistent with APO/ARDS were detectable in 5 of 45 admission chest X-rays performed (11.1%); the AUROCs were 0.86 (95% CI 0.74 to 0.99) for ALB and 0.91 (95% CI 0.82 to 0.99) for CRP/ALB. CONCLUSIONS: Diminished admission ALB levels and elevated CRP/ALB ratios are associated with disease severity and respiratory complications in imported falciparum malaria. These readily and ubiquitously available markers may facilitate early identification of at-risk patients.

The Colloid Osmotic Pressure Across the Glycocalyx: Role of Interstitial Fluid Sub-Compartments in Trans-Vascular Fluid Exchange in Skeletal Muscle.

The primary purpose of these investigations is to integrate our growing knowledge about the endothelial glycocalyx as a permeability and osmotic barrier into models of trans-vascular fluid exchange in whole organs. We describe changes in the colloid osmotic pressure (COP) difference for plasma proteins across the glycocalyx after an increase or decrease in capillary pressure. The composition of the fluid under the glycocalyx changes in step with capillary pressure whereas the composition of the interstitial fluid takes many hours to adjust to a change in vascular pressure. We use models where the fluid under the glycocalyx mixes with sub-compartments of the interstitial fluid (ISF) whose volumes are defined from the ultrastructure of the inter-endothelial cleft and the histology of the tissue surrounding the capillaries. The initial protein composition in the sub-compartments is that during steady state filtration in the presence of a large pore pathway in parallel with the "small pore" glycocalyx pathway. Changes in the composition depend on the volume of the sub-compartment and the balance of convective and diffusive transport into and out of each sub-compartment. In skeletal muscle the simplest model assumes that the fluid under the glycocalyx mixes directly with a tissue sub-compartment with a volume less than 20% of the total skeletal muscle interstitial fluid volume. The model places limits on trans-vascular flows during transient filtration and reabsorption over periods of 30-60 min. The key assumption in this model is compromised when the resistance to diffusion between the base of the glycocalyx and the tissue sub-compartment accounts for more than 1% of the total resistance to diffusion across the endothelial barrier. It is well established that, in the steady state, there can be no reabsorption in tissue such as skeletal muscle. Our approach extends this idea to demonstrate that transient changes in vascular pressure favoring initial reabsorption from the interstitial fluid of skeletal muscle result in much less fluid exchange than is commonly assumed. Our approach should enable critical evaluations of the empirical models of trans-vascular fluid exchange being used in the clinic that do not account for the hydrostatic and COPs across the glycocalyx.

Fluid and protein exchange in microvascular networks: Importance of modelling heterogeneity in geometrical and biophysical properties.

KEY POINTS: Microvascular network architecture defines coupling of fluid and protein exchange. Network arrangements markedly reduce capillary hydrostatic pressures and resting fluid movement at the same time as increasing the capacity for change The presence of vascular remodelling or angiogenesis puts constraints of network behaviour The sites of fluid and protein exchange can be segregated to different portions of the network Although there is a net filtration of fluid from a network of exchange vessels, there are specific areas where fluid moves into the circulation (reabsorption) and, when protein is moving into tissue, the amount is insufficient under basal conditions to result in changes in oncotic pressure. ABSTRACT: Integration of functional results obtained across scales, from chemical signalling to the whole organism, is a daunting task requiring the marriage of experimental data with mathematical modelling. In the present study, a novel coupled computational fluid dynamics model is developed incorporating fluid and protein transport using measurements in an in vivo frog (Rana pipiens) mesenteric microvascular network. The influences of network architecture and exchange are explored systematically under the common assumptions of structurally and functionally identical microvessels (Homogeneous Scenario) or microvessels classified by position in flow (Class Uniform Scenario), which are compared with realistic microvascular network components (Heterogeneous Scenario). The model incorporates ten quantities that vary within a microvessel; pressure boundary conditions are calibrated against experimental measurements. The Homogeneous Scenario standard model showed that assuming a single 'typical' capillary hides the influence of vessels arranged into a network architecture, where capillary hydrostatic pressures (pT ) are reduced, resulting in both a nonuniform distribution of blood flow and reduced volume flow rate (Jf,T ). In the Class Uniform Scenario pT was further attenuated to produce a ∼60% reduction in Jf,T . Finally, the Heterogeneous Scenario, incorporating measures of individual vessel surface area, demonstrates additional lowering of pT from inlet values favouring a >70% reduction of Jf,T in the face of a ∼120% increase in protein movement into the tissues relative to the Homogeneous Scenario. Beyond the impacts of network architecture, an unanticipated finding was the influence of a blind-end microvessel on model convergence, indicating a profound influence of the largely unexplored dynamics of vascular remodelling on tissue perfusion.

Preservation of renal endothelial integrity and reduction of renal edema by aprotinin does not preserve renal perfusion and function following experimental cardiopulmonary bypass.

BACKGROUND: Acute kidney injury is a severe complication following cardiopulmonary bypass (CPB) and is associated with capillary leakage and microcirculatory perfusion disturbances. CPB-induced thrombin release results in capillary hyperpermeability via activation of protease-activated receptor 1 (PAR1). We investigated whether aprotinin, which is thought to prevent thrombin from activating PAR1, preserves renal endothelial structure, reduces renal edema and preserves renal perfusion and reduces renal injury following CPB. METHODS: Rats were subjected to CPB after treatment with 33.000 KIU/kg aprotinin (n = 15) or PBS (n = 15) as control. A secondary dose of 33.000 KIU/kg aprotinin was given 60 min after initiation of CPB. Cremaster and renal microcirculatory perfusion were assessed using intravital microscopy and contrast echography before CPB and 10 and 60 min after weaning from CPB. Renal edema was determined by wet/dry weight ratio and renal endothelial structure by electron microscopy. Renal PAR1 gene and protein expression and markers of renal injury were determined. RESULTS: CPB reduced cremaster microcirculatory perfusion by 2.5-fold (15 (10-16) to 6 (2-10) perfused microvessels, p < 0.0001) and renal perfusion by 1.6-fold (202 (67-599) to 129 (31-292) au/sec, p = 0.03) in control animals. Both did not restore 60 min post-CPB. This was paralleled by increased plasma creatinine (p < 0.01), neutrophil gelatinase-associated lipocalin (NGAL; p = 0.003) and kidney injury molecule-1 (KIM-1; p < 0.01). Aprotinin treatment preserved cremaster microcirculatory perfusion following CPB (12 (7-15) vs. 6 (2-10) perfused microvessels, p = 0.002), but not renal perfusion (96 (35-313) vs. 129 (31-292) au/s, p > 0.9) compared to untreated rats. Aprotinin treatment reduced endothelial gap formation (0.5 ± 0.5 vs. 3.1 ± 1.4 gaps, p < 0.0001), kidney wet/dry weight ratio (4.6 ± 0.2 vs. 4.4 ± 0.2, p = 0.046), and fluid requirements (3.9 ± 3.3 vs. 7.5 ± 3.0 ml, p = 0.006) compared to untreated rats. In addition, aprotinin treatment reduced tubulointerstitial neutrophil influx by 1.7-fold compared to untreated rats (30.7 ± 22.1 vs. 53.2 ± 17.2 neutrophil influx/section, p = 0.009). No differences were observed in renal PAR1 expression and plasma creatinine, NGAL or KIM-1 between groups. CONCLUSIONS: Aprotinin did not improve renal perfusion nor reduce renal injury during the first hour following experimental CPB despite preservation of renal endothelial integrity and reduction of renal edema.

Atrial natriuretic peptide does not degrade the endothelial glycocalyx: A secondary analysis of a randomized porcine model.

BACKGROUND: The atrial natriuretic peptide (ANP) released from the heart regulates intravascular volume and is suspected to increase capillary permeability. Contradictory results regarding ANP and glycocalyx degradation have been reported. The aim of this study was to investigate if an infusion of ANP causes degradation of the endothelial glycocalyx. METHODS: Twenty pigs, pretreated with 250 mg methylprednisolone, were randomized to receive an infusion of either ANP (50 ng/kg/min) (n = 10) or 0.9% NaCl (n = 10) during 60 min. Endothelial glycocalyx components (heparan sulphate proteoglycan and hyaluronic acid), Hct, calculated plasma volume and colloid osmotic pressure were measured from baseline to 60 min. RESULTS: There was no difference between the control and intervention groups for heparan sulphate proteoglycan and hyaluronic acid corrected for the change in plasma volume (P = .333 and 0.197). Hct increased with 1.8 ± 2.2% in the intervention group (P = .029) with no change -0.5 ± 2.3% in the control group (P = .504). The plasma volume decreased in the intervention group with -8.4 ± 10% (P = .034) with no change in the control group 3.1 ± 12% (P = .427). Median changes in colloid osmotic pressures in the control and intervention group were -0.39 [95% CI, -1.88-0.13] and 0.9 [95% CI, 0.00-1.58], respectively (P = .012). CONCLUSIONS: In this randomized porcine study, an ANP infusion did not cause endothelial glycocalyx degradation but decreased the plasma volume most probably due to precapillary vasodilation and increased filtration.

Drug-induced peripheral oedema: An aetiology-based review.

Many drugs are responsible, through different mechanisms, for peripheral oedema. Severity is highly variable, ranging from slight oedema of the lower limbs to anasarca pictures as in the capillary leak syndrome. Although most often noninflammatory and bilateral, some drugs are associated with peripheral oedema that is readily erythematous (eg, pemetrexed) or unilateral (eg, sirolimus). Thus, drug-induced peripheral oedema is underrecognized and misdiagnosed, frequently leading to a prescribing cascade. Four main mechanisms are involved, namely precapillary arteriolar vasodilation (vasodilatory oedema), sodium/water retention (renal oedema), lymphatic insufficiency (lymphedema) and increased capillary permeability (permeability oedema). The underlying mechanism has significant impact on treatment efficacy. The purpose of this review is to provide a comprehensive analysis of the main causative drugs by illustrating each pathophysiological mechanism and their management through an example of a drug.

Hypoalbuminemia in COVID-19: assessing the hypothesis for underlying pulmonary capillary leakage.

BACKGROUND: Since the first observations of patients with COVID-19, significant hypoalbuminaemia was detected. Its causes have not been investigated yet. OBJECTIVE: We hypothesized that pulmonary capillary leakage affects the severity of respiratory failure, causing a shift of fluids and proteins through the epithelial-endothelial barrier. METHODS: One hundred seventy-four COVID-19 patients with respiratory symptoms, 92 admitted to the intermediate medicine ward (IMW) and 82 to the intensive care unit (ICU) at Luigi Sacco Hospital in Milan, were studied. RESULTS: Baseline characteristics at admission were considered. Proteins, interleukin 8 (IL-8) and interleukin 10 (IL-10) in bronchoalveolar lavage fluid (BALF) were analysed in 26 ICU patients. In addition, ten autopsy ultrastructural lung studies were performed in patients with COVID-19 and compared with postmortem findings in a control group (bacterial pneumonia-ARDS and H1N1-ARDS). ICU patients had lower serum albumin than IMW patients [20 (18-23) vs 28 (24-33) g L-1 , P < 0.001]. Serum albumin was lower in more compromised groups (lower PaO2 -to-FiO2 ratio and worst chest X-ray findings) and was associated with 30 days of probability of survival. Protein concentration was correlated with IL-8 and IL-10 levels in BALF. Electron microscopy examinations of eight out of ten COVID-19 lung tissues showed loosening of junctional complexes, quantitatively more pronounced than in controls, and direct viral infection of type 2 pneumocytes and endothelial cells. CONCLUSION: Hypoalbuminaemia may serve as severity marker of epithelial-endothelial damage in patients with COVID-19. There are clues that pulmonary capillary leak syndrome plays a key role in the pathogenesis of COVID-19 and might be a potential therapeutic target.

Progress in anti-inflammatory effects of escin / 中国药理学与毒理学杂志

The fraction of horse chestnut seeds was named escins, which mainly consists of A, B, C, and D escin. Accumulating evidence suggests that escin exerts potent anti-inflammatory and anti-edematous effects. The effects of escin on inflammation and edema have been confirmed in various models. In a study in 1961, intravenous administration of escin was found to reduce acute edema in a rat paw. In the same study, escin was found to inhibit the increase in vascular permeability induced by egg white injection. Escin dose-dependently reduced the capillary permeability in chlo?roform-induced local inflammation in the abdominal skin surface of rabbits. The anti-inflammatory and anti-edematous effects of external use of escin were studied in carrageenan-induced paw edema and histamine-induced capillary perme?ability in rats. Escin gel decreased the contents of PGE2, TNF-α, and IL-1β, and reduced the raw edema and capillary permeability. The carrageenan-induced paw edema and pleuritis in bilaterally adrenalectomized rats were used to inves?tigate the anti-inflammatory effects of escin and glucocorticoid alone or combined. Co-administration of escin with corti?sone significantly reduced the volume of exudates and the number of white blood cells of exudates. The findings sug?gest escin can synergize with glucocorticoids to enhance their anti-inflammatory effect. The anti-inflammatory effect of escin was investigated in carrageenan-induced paw edema and acetic acid-induced capillary permeability in mice. Escin showed an anti-inflammatory effect, which is similar to that seen with dexamethasone treatment. However, escin showed a longer duration of the anti-inflammatory response than that of dexamethasone. Furthermore, escin had no signif?icant effects on spleen index, thymus index , proliferative capacity of splenocytes, lymphocyte count, and phagocytic rate. The findings suggest that escin is a potent anti-inflammatory drug with long-lasting anti-inflammatory effects without any immunosuppressive effects. Traditionally the mechanism of anti-inflammatory effect of escin is supposed to be rela?tive to release of PGF2α and corticosterone. The early studies showed that escin might promote the release of PGF2αand affect the pituitary adrenal system, stimulate the release of adrenocorticotropic hormone (ACTH) and glucocorticoid, which may explain its anti-inflammatory and anti-edema effects. Escin has glucocorticoid-like anti-inflammatory effect. However, escin did not exhibit an anti-inflammatory effect in low dose. Combination of suboptimal concentrations of escin with corticosterone inhibited the release of inflammatory factors including NO, TNF-αand IL-1βin the LPS-stimulated macrophage cells. Previous studies demonstrate that escin combined with glucocorticoid produced synergistic anti-inflammatory effects. The potential synergistic mechanisms may be associated with the property which escin regulates the glucocorticoid receptor (GR) signaling pathway. Escin can upregulate the expression of GR, promote the combina?tion of glucocorticoid and GR, then promote the activated GR transfer into the nucleus. Activated GR will inhibit the acti?vation of NF-κB directly, thus further inhibiting the expression of TNF-αand IL-1βand other inflammatory factors. Escin could inhibit 11β-HSD2 but not 11β-HSD1, thus decrease the metabolism of glucocorticoid. Escin and glucocorticoids have similar chemical structures. This indicate that one of the anti-inflammatory mechanisms of escin may be due to its stimulating GR by binding to it. Eacin might be a partial agonist of GR. A good many of researches have demonstrated the anti-inflammatory properties of escin, and shed light on the underlying mechanisms by which escin exerts these effects. Escin, as an oral or intravenous formulation, or a topical gel, inhibits inflammation, producing measurable improve?ments in edema and acute lung injury. Further clinical studies of escin are needed to demonstrate these properties in larger patient populations.

Estudo da Reatividade Microvascular em Pacientes Hipertensos com Adiposidade Corporal Elevada / Microvascular Reactivity in Hypertensive Patients with High Body Adiposity

Resumo Fundamento: Diversos índices antropométricos têm sido propostos para determinar a associação entre excesso de peso e fatores de risco cardiovascular. Objetivo: Avaliar a relação entre adiposidade corporal e reatividade microvascular em pacientes hipertensos sob terapia anti-hipertensiva. Métodos: Pacientes hipertensos tratados de 40 a 70 anos foram submetidos à avaliação de índices antropométricos: conicidade (IC), adiposidade corporal (IAC), adiposidade visceral (IAV) e relação cintura-estatura (RCE). Os participantes foram divididos pelos tercis de percentual de gordura (%G) obtido pela bioimpedância elétrica (BIA) e submetidos a teste de reatividade microvascular (laser speckle contrast image), medida da velocidade da onda de pulso (VOP). O valor de p < 0,05 foi considerado estatisticamente significativo. Resultados: A variação da área sob a curva (ASC) da perfusão cutânea foi inferior no tercil superior (97 ± 57% vs. 67 ± 36%; p = 0,027). O %G apresentou correlação significativa com RCE (r = 0,77; p < 0,001), IAV (r = 0,41; p = 0,018), IC (r = 0,60; p < 0,001) e IAC (r = 0,65; p < 0,001) nos homens e somente com RCE (r = 0,55; p < 0,001) e IAC (r = 0,60; p < 0,001) nas mulheres. Na regressão linear, a ASC mostrou associação independente com o %G (β =-3,15; p = 0,04) nas mulheres e com a glicemia (β = -1,15; p = 0,02) nos homens. Não houve diferença nas medidas de VOP. Conclusão: Os índices antropométricos de obesidade foram mais associados ao %G nos homens. A maior adiposidade corporal foi relacionada com menor reatividade microvascular, o que foi mais evidente nas mulheres. Não houve diferença na rigidez arterial, o que pode ter sido influenciado pelo tratamento anti-hipertensivo.

Abstract Background: Several anthropometric indexes have been proposed to determine the association between overweight and cardiovascular risk factors. Objective: To evaluate the relationship between body adiposity and microvascular reactivity in hypertensive patients under antihypertensive therapy. Methods: Treated hypertensive patients aged 40 to 70 were submitted to evaluation of anthropometric indexes: conicity (CI), body adiposity (BAI), visceral adiposity (VAI) and waist-to-height ratio (WHtR). Participants were divided by the terciles of fat percentage (%F) obtained by bioelectrical impedance. The patients underwent microvascular reactivity test (Laser Speckle Contrast Image) and pulse wave velocity (PWV) measurement. The p value <0.05 was considered statistically significant. Results: The variation of the area under the curve (AUC) of the skin perfusion was lower in the upper tercile (97±57% vs. 67±36%; p=0.027). %F showed significant correlation with WHtR (r=0.77; p<0.001), VAI (r=0.41; p=0.018), CI (r=0.60; p<0.001), BAI (r=0.65; p<0.001) in men and only with WHtR (r=0.55; p<0.001) and BAI (r=0.60; p<0.001) in women. In linear regression, AUC was independently associated with %F (β=−3.15; p=0.04) in women and with blood glucose (β=−1.15; p=0.02) in men. There was no difference in PWV measurements. Conclusion: Anthropometric indices were more associated with %F in men. Higher body adiposity was associated with lower microvascular reactivity, which was more evident in women. There was no difference in arterial stiffness, which may have been influenced by antihypertensive treatment.

Hypotension and Bradycardia Produced by Transthoracic Application of Low-Intensity Ultrasound Therapy in Hearts of Healthy Rats - A Preclinical Study.

OBJECTIVE: To investigate the cardiovascular effects produced by transthoracic application of low-intensity pulsed ultrasound therapy (LIPUST). METHODS: Three-month-old male Wistar rats (± 300 g, N=16) were randomly allocated in two groups, namely SHAM (control group, faked procedures) and UST (animals treated with LIPUST). These animals, under anesthesia, were instrumented (femoral artery and vein catheterization) for hemodynamic recordings (mean blood pressure [MBP], heart rate [HR]) and blood biochemical profile (lipids, creatine kinase-myocardial band [CK-MB]). Then, LIPUST (spatial average-temporal average [ISATA] 1-MHz, power 0.1 to 1.2 W/cm2, pulsed 2:8 ms, cycle at 30%, for three minutes) was applied to animals from the UST group, externally to their thorax. SHAM animals were equally manipulated, but without application of ultrasound energy. After the hemodynamic and biochemical measurements, animals were sacrificed, and their hearts were mounted in a Langendorff apparatus for coronary reactivity evaluation. Standard histology techniques were employed to analyze the hearts. RESULTS: LIPUST application caused statistically significant reductions in MBP (92±4 vs. 106±1 mmHg) and HR (345±14 vs. 380±17 rpm) when compared with SHAM procedures. UST rats exhibited higher CK-MB levels (318±55 vs. 198±26 U/dL) and lower plasma triglycerides levels (38±7 vs. 70±10 mg/dL) than SHAM animals. Coronary reactivity was not significantly changed by LIPUST. Cardiac histopathology showed an increase in capillary permeability in treated animals when compared with SHAM animals. CONCLUSION: Noninvasive LIPUST induces significant metabolic and hemodynamic changes, including intensity-dependent bradycardia and hypotension, indicating a possible therapeutic effect for cardiac events.

[Research advances on the molecular mechanisms of vascular permeability in sepsis].

Sepsis is one of the critical illnesses caused by burns, trauma, shock, infection, and so on. In patients with sepsis, vascular permeability is prone to develop through various pathophysiological mechanisms and thus could result in accumulation of tissue fluid, insufficient intravascular fluid, and finally cause septic shock and multiple organ dysfunction syndrome. Recent studies have shown that various factors and mediators involved in the regulation of vascular permeability in sepsis are expected to become targets for clinical treatment of sepsis. In this paper, we have reviewed the research advances on some molecules which are significantly associated with vascular permeability in sepsis, such as vascular endothelial growth factor, angiopoietin, sphingosine-1-phosphate, heparin-binding protein, and Slit2.