Dual role for plasminogen activator inhibitor type 1 as soluble and as matricellular regulator of epithelial alveolar cell wound healing

Epithelium repair, crucial for restoration of alveolo-capillary barrier integrity, is orchestrated by various cytokines and growth factors. Among them keratinocyte growth factor plays a pivotal role in both cell proliferation and migration. The urokinase plasminogen activator (uPA) system also influences cell migration through proteolysis during epithelial repair. In addition, the complex formed by uPAR-uPA and matrix-bound plasminogen activator inhibitor type-1 (PAI-1) exerts nonproteolytic roles in various cell types. Here we present new evidence about the dual role of PAI-1 under keratinocyte growth factor stimulation using an in vitro repair model of rat alveolar epithelial cells. Besides proteolytic involvement of the uPA system, the availability of matrix-bound-PAI-1 is also required for an efficient healing. An unexpected decrease of healing was shown when PAI-1 activity was blocked. However, the proteolytic action of uPA and plasmin were still required. Moreover, immediately after wounding, PAI-1 was dramatically increased in the newly deposited matrix at the leading edge of wounds. We thus propose a dual role for PAI-1 in epithelial cell wound healing, both as a soluble inhibitor of proteolysis and also as a matrix-bound regulator of cell migration. Matrix-bound PAI-1 could thus be considered as a new member of the matricellular protein family.     

Risk factors for COVID-19-related death,hospitalization and intensive care: a population-wide study of all inhabitants in Stockholm

European Journal of Epidemiology - Since the beginning of the Covid-19 pandemic, the scientific community has explored determinants of Covid 19 disease severity. However, the majority of studies...     

Damaging effects of gliadin on three-dimensional cell culture model

AIM: To evaluate the effects of gliadin on the oxidative environment in the "in vivo-like" model of a three-dimensional cell culture system. METHODS: LoVo cell line (intestinal adenocarcinoma) multicellular spheroids were treated with digested gliadin (with albumin used as a control). Spheroid volumes, cell viability and morphology, lactate dehydrogenase (LDH) release, content of reduced glutathione (GSH) and activity of GSH-related enzymes were examined. The data were statistically analyzed using the Student's t-test (P<0.05). was considered statistically significant. RESULTS: Gliadin reduced cell viability (from 20% to 60%) and led to morphological alterations characterized by apoptotic findings and cytoskeletal injuries. LDH activity increased. The content of GSH reduced (-20% vs controls), and activity of GSH-related enzymes was significantly inhibited. CONCLUSION: Gliadin treatment induces an imbalance in the antioxidative mechanism of cells cultured by the three-dimensional technique. This alteration may explain the cell damage directly caused by gliadin and the subsequent morphological abnormalities.     

The role of secretory IgA and complement in IgA nephropathy

IgA nephropathy (IgAN) is characterized by glomerular deposition of IgA, often together with complement components. This deposited IgA is mainly polymeric in nature. Although early studies suggested a role for local complement activation in the development of glomerular injury in IgAN, recent attention has focused on the involvement of the lectin pathway of complement activation in the progression of renal disease in IgAN. In addition, we have found that glomerular secretory IgA deposition may be one of the initiators of local complement activation in the kidney. In the present review we discuss recent developments in this area and provide a model of how mucosal immunity and renal inflammation may be interconnected.     

EEG cortical potentials preceding vergence and combined saccade-vergence eye movements

Previous event-related potential (ERP) studies of eye movements were restricted to saccades, the rapid conjugate movements used to change direction of fixation. Our study explored ERP activity for vergence eye movements used for the adjustment of the angle of the visual axes to the distance of the object. These movements are essential when exploring the natural 3D world. Subjects made the following visually guided movements to LED targets: pure convergence or divergence along the median plane, pure lateral saccades within the same distance, and combined movements (lateral and divergent or convergent). ERPs were recorded from 14 surface electrodes and were analyzed for 200 ms prior to the onset of the eye movement. The highest activation was observed prior to vergence. Activation was diffused and peaked at 50 ms prior to the onset of vergence. Combined vergence and sacccadic movements revealed a composite pattern of ERP activity from both saccades and pure vergence. These findings suggest a cortical substrate for vergence eye movements in humans that is engaged in the natural exploration of visual space.     

Swedish moist snuff and myocardial infarction among men

BACKGROUND: Previous studies have provided inconsistent results on possible increased risk of cardiovascular disease with the use of smokeless tobacco. The aim of this study was to assess whether long-term use of Swedish moist snuff (widely used among Swedish men) increases the risk of acute myocardial infarction. METHODS: This case-control study was conducted in 2 Swedish counties. We identified 1760 men, age 45-70 years, who had a myocardial infarction in 1992-1994. We randomly selected male controls from the study base after stratification for age and hospital catchment area. Information about snuff consumption, smoking history, hypertension, and other factors was obtained by mailed questionnaire and medical examination. The participation rate was 77% among cases and 78% among controls, with tobacco use data available for 1432 cases and 1810 controls. RESULTS: After adjustment for age, hospital catchment area, and smoking, the relative risk of first acute myocardial infarction was 1.1 (95% confidence interval=0.8-1.5) for former snuff users and 1.0 (0.8-1.3) for current snuff users. Analyses limited to either nonfatal or fatal cases did not change the results. Among the controls, the consumption of smokeless tobacco was strongly associated with certain risk factors for myocardial infarction such as smoking, hypertension, and high body mass index. CONCLUSION: The hypothesis that smokeless tobacco increases the risk for myocardial infarction is not supported in the present study.     

Harnessing Type I IFN Immunity Against SARS-CoV-2 with Early Administration of IFN-β

Journal of Clinical Immunology -