Tissue plasminogen activator attenuates ventilator-induced lung injury in rats

Abstract

Aim: To test the hypothesis that the tissue plasminogen activator (tPA) may counteract the inhibitory effect of plasminogen activator inhibitors (PAI) and attenuate lung injury in a rat model of ventilator-induced lung injury (VILI). Methods: Adult male Sprague-Dawley rats were ventilated with a HVZP (high-volume zero PeeP) protocol for 2 h at a tidal volume of 30 mL/kg, a respiratory rate of 25 breaths/min, and an inspired oxygen fraction of 21%. The rats were divided into 3 groups (n=7 for each): HVZP+tPA group receiving tPA (1.25 mg/kg, iv) 15 min before ventilation, HVZP group receiving HVZP+vehicle injection, and a control group receiving no ventilation. After 2 h of ventilation, the rats were killed; blood and lungs were collected for biochemical and histological analyses. Results: HVZP ventilation significantly increased total protein content and the concentration of macrophage inflammatory protein-2 (MIP-2) in the bronchoalveolar lavage fluid (BALF) as well as the lung injury score. Rats that received HVZP ventilation had significantly higher lung PAI-1 mRNA expression, plasma PAI-1 and plasma D-dimer levels than the control animals. tPA treatment significantly reduced the BALF total protein and the lung injury score as compared to the HVZP group. tPA treatment also significantly decreased the plasma D-dimer levels and the HVZP ventilation-induced lung vascular fibrin thrombi. tPA treatment showed no effect on MIP-2 level in BALF.Conclusion: These results demonstrate that VILI increases lung PAI-1 mRNA expression, plasma levels of PAI-1 and D-dimers, lung injury score and vascular fibrin deposition. tPA can attenuate VILI by decreasing capillary-alveolar protein leakage as well as local and systemic coagulation as shown by decreased lung vascular fibrin deposition and plasma D-dimers.

Valproic Acid in Prevention and Treatment of COVID-19

“…[39] Ventilator-induced lung injury is another cause in COVID-19 death and T-PA is known to attenuate ventilator-induced lung injury. [41] Overall, VPA-induced T-PA appears to be beneficial to the COVID-19 patients due to its anti-thrombotic activity and attenuation of ventilatorinduced lung injury function. COX-2 was also up-regulated in VPA-treated ECs.…”

Meta-Analysis of Preclinical Studies of Fibrinolytic Therapy for Acute Lung Injury

“…General characteristics of these 22 studies were summarized in Table 1 . Ten studies were performed for tPA (0.098–250 mg) ( 15 , 16 , 19 , 20 , 22 , 24 , 27 – 30 ), seven for uPA (up to 240 mg or 2,230,000 IU) ( 18 , 21 , 25 , 32 – 35 ), three for plasmin (0.5 mg or 100,000 IU) ( 37 – 39 ), and two in gene therapeutic mice by either over expressing uPA ( 36 ) or tPA ( 31 ). The geological distributions of these studies are: 10 from USA (48%) ( 15 , 16 , 25 , 27 – 30 , 32 , 36 , 37 ), 4 from Netherlands (17%) ( 19 , 20 , 24 , 31 ), 4 from China (17%) ( 22 , 33 – 35 ), 2 from Japan (9%) ( 38 , 39 ), 1 from Germany (4%) ( 18 ), and 1 from Denmark ( 21 ).…”

“…Fifteen papers were published in small animals. Twelve studies were conducted in rodents: 2 in mice ( 31 , 36 ) and 10 in rats ( 19 , 20 , 22 , 24 , 27 – 30 , 38 , 39 ). In addition, 3 studies used rabbits ( 18 , 34 , 35 ).…”

“…When only graphic presentations were available, values for mean and SD were obtained via calibrating images using GetData Graph Digitizer software (version 2.26.0.20) ( 18 – 20 ). If raw data were represented by median and interquartile range ( 20 , 21 ) or range ( 22 ), these values were converted to SD by the formulas: SD 2 = 1/12 [(a − 2 m + b) 2 /4 + (b − a) 2 ], and mean = (a + 2 m + b)/4, where m represents median, a and b are lower and upper range ( 23 ). If the SE was reported ( 20 ), it was converted to SD using the function, , where n is the sample size.…”

Deferoxamine preconditioning ameliorates mechanical ventilation-induced lung injury in rat model via ROS in alveolar macrophages: a randomized controlled study

“…At present, biological lung injury is known to be associated with the release of inflammatory factors, apoptosis, endothelial injury, and activation of the coagulation system [ 3 , 4 ]. However, the existing therapeutic effect is limited targeting the above mechanisms.…”