Adhesion and transcellular migration of neutrophils and B lymphocytes on fibroblasts

During tissue inflammation, infiltrated leukocytes may have physical contacts with fibroblasts. We observed that neutrophils and B lymphocytes adhered in a larger proportion than T cells on cultured fibroblasts. Microscopy showed that adhesion was also characterized by leukocyte engulfment by the fibroblasts. In migration assays, only neutrophils and B lymphocytes were selectively able to migrate through a fibroblast barrier. Adhesion and migration were increased by stimulation with tumor necrosis factor-alpha (TNF-alpha) and phorbol-12-myristate-13-acetate (PMA). Antibodies against ICAM-1/beta2 integrin blocked the interaction of neutrophils to fibroblasts. For B lymphocytes the couple VCAM-1/alpha4 integrin was also involved in this interaction. Human skin fibroblasts presented similar adhesion characteristics as rat cardiac fibroblasts. By measuring the distance between the border of migration holes and cadherin-positive adherens junctions, more than 65% of the holes correspond to the transcellular route over the paracellular route. Furthermore, vimentin staining revealed that the migration holes were highly nested by intermediate filaments in accordance with the transcellular route. Our results demonstrated that engulfment of neutrophils and B lymphocytes by fibroblasts resulted in selective passage by a transcellular route.This work was supported by grants from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Counci

Evidence for intracellular generation of angiotensin II in rat juxtaglomerular cells

AbstractThe formation of the vasoactive peptide angiotensin II (AII) is dependent on the sequential action of two enzymes, renin and angiotensin converting enzyme (ACE), on the substrate angiotensinogen. Although the renin-producing cells of the kidney do not express angiotensinogen, they contain large amounts of AII in the same storage granules that contain renin. When renin expression is suppressed in these cells, AII also disappears. In the current study, we have tested whether the renin-associated disappearance of AII in renal juxtaglomerular (JG) cells is due to a renin-dependent down-regulation of granule biosynthesis and whether receptor-mediated internalization of AII could account for its concentration in these cells. Our results support a model whereby AII peptides are generated within JG cells, presumably by a mechanism which involves the action of endogenous renin on internalized, exogenous angiotensinogen

Role of the liver in splanchnic extraction of atrial natriuretic factor in the rat

Mesenteric, hepatic and splanchnic extraction of C-terminal and N-terminal atrial natriuretic factor was investigated in male Sprague-Dawley rats. Plasma concentrations (mean ± S.E.M.) of C-terminal atrial natriuretic factor were 55.0 ± 6.1 fmol/ml, 31.2 ± 4.0 fmol/ml and 23.5 ± 3.3 fmol/ml (n = 12) in the abdominal aorta, the portal vein and the hepatic vein, respectively. N-terminal atrial natriuretic factor plasma levels in these vessels were 3031 ± 756 fmol/ml, 2264 ± 661 fmol/ml and 1618 ± 496 fmol/ml (n = 6), respectively. Although the mesenteric extraction ratio was higher (p < 0.05) for C-terminal atrial natriuretic factor (42% ± 6%) than for N-terminal atrial natriuretic factor (28% ± 4%), there were no significant differences in the hepatic extraction ratio (41% ± 5% vs. 39% ± 6%) and the splanchnic extraction ratio (56% ± 5% vs. 50% ± 7%). These data suggest a major role of the liver in the splanchnic extraction of C-terminal and of N-terminal atrial natriuretic factor in the rat. (HEPATOLOGY 1992;16:790-793

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction : le sport et l'activité physique, éléments centraux de la vie personnelle, communautaire, sociale et économique - Introduction : sports and physical activity, key elements of personal, community, social and economic life

Introduction du numéro thématique : 'Sport et activité physique : vie personnelle, sociale et économique'

Comparative specificity of platelet IIb3 integrin antagonists. J Pharmacol Exp Ther 296: 690–606

ABSTRACT Several platelet ␣ IIb ␤ 3 integrin antagonists have been designed as preventive agents against the formation of arterial thrombi. Although the potency of these compounds in inhibiting platelet aggregation is in the nanomolar range, their specificity on other integrins that can bind ligands through an arginine-glycineaspartic acid (RGD) motif is far from being well established. For instance, some cyclic RGD peptides can also interact with ␣ v ␤ 3 integrin. We used a novel pharmacological assay, based on SDS-stable interaction between 125 I-echistatin and RGD-dependent integrins, to evaluate the specificity of several RGD compounds on integrins present on rat cardiac fibroblasts and human skin fibroblasts. None of the RGD peptidomimetics tested (L-734,217, lamifiban, Ro 44-3888, SR 121566A, BIBU-52, XV459) could interact with either ␣ v ␤ 3 and ␣ 8 ␤ 1 on rat fibroblasts or with ␣ v ␤ 3 and ␣ v ␤ 1 on human fibroblasts. Cyclic RGD peptides showed some potency (3-80 M) on rat and human integrins with an ␣ v subunit. We also compared the potency of these compounds on platelets. All RGD compounds demonstrated IC 50 between 0.6 and 530 nM on basal human platelets. Activation of the receptor with thrombin resulted in a 2-to 60-fold increase in potency, with L-734,217 and BIBU-52 showing the largest difference. On basal and thrombin-activated rat platelets, only eptifibatide, DMP728, and XJ735 could displace 125 I-echistatin (IC 50 Ϸ 0.1-1.5 M). These results indicate that RGD peptidomimetics have a specificity limited to ␣ IIb ␤ 3 integrin, whereas cyclic RGD peptides can also interact with other RGD-dependent integrins, particularly those of the ␣ v subunit family