Paroxysmal Permeability Disorders: Development of a Microfluidic Device to Assess Endothelial Barrier Function

Abstract

Background: Paroxysmal Permeability Disorders (PPDs) are pathological conditions caused by periodic short lasting increase of endothelial permeability, in the absence of inflammatory, degenerative, ischemic vascular injury. PPDs include primary angioedema, idiopathic systemic capillary leak syndrome and some rare forms of localized retroperitoneal-mediastinal edema. Aim: to validate a microfluidic device to study endothelial permeability in flow conditions. Materials and Methods: we designed a microchannel network (the smallest channel is 30μm square section). Human Umbilical Vein Endothelial Cells (HUVECs) were cultured under constant shear stress in the networks. Endothelial permeability assessment was based on interaction of biotinylated fibronectin used as a matrix for HUVECs and FITC-conjugated avidin. The increase in endothelial permeability was identified as changes in fluorescence intensity detected by confocal fluorescent microscopy. Results: The microchannels were constantly perfused with a steady flow of culture medium, ensuring a physiologically relevant level of shear stress at the wall of ~0.2 Pa. Our preliminary results demonstrated that circulation of culture medium or plasma from healthy volunteers was associated with low fluorescence of fibronectin matrix. When bradykinin diluted in culture medium was perfused, an increase in average fluorescence was detected. Conclusion: Our microvasculature model is suitable to study endothelial functions in physiological flow conditions and in the presence of factors like bradykinin known as mediator of several PPDs. Therefore, it can be a promising tool to better understand the mechanisms underlying disorders of endothelial permeability.

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

“…Lower albumin values were found in patients with more severe respiratory involvement (expressed as either lower PaO 2 -to-FiO 2 ratio or higher CXR score) (Figure 2a). Median serum albumin was 31 (27)(28)(29)(30)(31)(32)(33) g L À1 in patients with PaO 2 -to-FiO 2 ratio > 250, 24 (20.75-27.5) g L À1 in those with PaO 2 -to-FiO 2 ratio between 150 and 250, and 20 (18-24) g L À1 g L À1 in those with PaO 2 -to-FiO 2 ratio < 150. Serum albumin concentration was significantly lower in patients with chest X-ray showing more diffuse and pronounced pulmonary involvement (P < 0.0001) (Figure 2b): serum albumin was 31 (26.75-35.25) g L À1 with CXR score < 5, 27 (24-32) g L À1 with CXR score between 6 and 11, and 21 (18-24) g L À1 with CXR score ≥ 12.…”

“…The condition may stem from a variety of underlying clinical conditions and pathophysiological mechanisms. In a minority of cases, capillary leakage is considered to be the primum movens of the clinical condition, with no identifiable endothelial injury and has transient features as in the idiopathic systemic capillary leak syndrome (ISCLS), belonging to the group of Paroxysmal Permeability Disorders (PPDs) [27]. Either primary or secondary capillary leak syndrome might be associated with a variety of clinical pictures, ranging from asymptomatic states to generalized oedema and life‐threatening multiple organ failure, requiring urgent intervention.…”

COVID-19: the key role of pulmonary capillary leakage. An observational cohort study

“…The condition may stem from a variety of underlying clinical conditions and pathophysiological mechanisms: haematological diseases and their complications, drugs and toxic agents (chemotherapy, interleukin 2, Granulocyte-Macrophage Colony-Stimulating Factor, interferon, venom, carbon monoxide), post-surgery and post-trauma states, systemic syndromes (i.e., haemophagocytic lymphohistiocytosis, engraftment syndrome, ovarian hyperstimulation syndrome, differentiation syndrome), dermatologic diseases, infections. In a minority of cases, capillary leakage is considered to be the primum movens of the clinical condition, with no identifiable endothelial injury and has transient features: this nosological entity gathers a variety of conditions which are grouped under the denomination of Paroxysmal Permeability Disorders (PPDs) and include primary angioedema, idiopathic systemic capillary leak syndrome (ISCLS), and some rare forms of localised retroperitoneal-mediastinal oedema (23). A variety of clinical pictures may be due to either primary or secondary capillary leak syndrome, ranging from asymptomatic states to generalised oedema and life-threatening multiple organ failure, requiring urgent intervention.…”

Molecular Dambusters: What Is Behind Hyperpermeability in Bradykinin-Mediated Angioedema?

“…Wu et al . proposed to name these transient conditions as paroxysmal permeability disorders (PPDs), characterized by the return of the ECs to normal function after resolution of the angioedema attack [ 6 , 7 ].…”