No – blood clots, yes – normal clotting
One of the largest and most important processes in the human body is inflammation. The inflammatory response to injury or disease helps the immune system to win the fight for the health of the body. But an inflammatory reaction can lead to extremely adverse consequences: in response, the synthesis of thrombin can sharply increase, which will lead to increased thrombosis. Activated protein C (APC), a natural anticoagulant with anti-inflammatory and other protective properties, is used in medical practice to treat wounds and foci of infection in order to reduce inflammation of vascular endothelial cells. But its use is limited, since an excess of APS can excessively suppress clotting and lead to bleeding.
A group of researchers from Beth Israel Deaconess Medical Center (BIDMC) and the Wyss Institute at Harvard University found that artificial APC-like molecules called parmodulins provide the same anti-inflammatory and anticoagulation protection of endothelial cells as natural APC, but they do not interfere with normal blood clotting processes.. This makes parmodulins attractive for considering them as the active ingredient of a new drug. The discovery was made possible thanks to the "organ on a chip" technology developed at the Wyss Institute and modeling of thrombosis in a blood vessel in vitro.
The study not only proved the protective effect of parmodulins on the endothelium, but also determined its mechanism.
The target for APS and parmodulins is the transmembrane protein protease-activated receptor-1 (protease-activated receptor 1, PAR1). It is present on vascular endothelial cells and platelets circulating in the blood, and increases blood clotting. Activation of PAR1 on endotheliocytes by APS protein is accompanied by anti-inflammatory, anti-apoptotic effects and a decrease in vascular wall permeability. In combination, it protects cells from the pathological effects of inflammation.
In addition to activating PAR1, APS directly inhibits the production of thrombin, which is an important component of normal blood clotting processes. Excessive blocking of thrombin leads to bleeding. The absence of the effect of parmodulins on thrombin could make them a safer alternative to APS.
To assess the effect of parmodulins on the endothelium, the researchers incubated in vitro human vascular endotheliocytes with parmodulin-2 for 4 hours. After that, they were exposed to thrombin-inducing inflammatory agents: lipopolysaccharide or tumor necrosis factor (TNF-alpha). In samples with parmodulin, the ability of both agents to generate thrombin was 50% lower compared to control samples. At the same time, parmodulin-2 did not block the action of factors V and X – proteins involved in the normal clotting process.
In order to confirm the effect of parmodulins on inflammation, the researchers used a "blood vessel on a chip" consisting of microfluidic channels embedded in a polymer chip, coated with collagen and lined with endothelial cells. To simulate natural blood flow and evaluate the endothelial response, blood with pro- and anti-inflammatory compounds was passed through a chip.
Source: Wyss Institute at Harvard University
In the experiment, TNF-alpha was injected into the blood. Platelets accumulated on the endothelium – this is a typical response to inflammation. In the presence of parmodulin-2, platelet accumulation did not occur, the endothelium functioned normally. The obtained results proved that parmodulin-2 inhibits inflammation in the form of a thrombotic reaction.
In other experiments, it was proved that parmodulins, activating PAR1, trigger cytoprotective (protective) reactions of endothelial cells by suppressing apoptosis (programmed cell death). This is due to the suppression of thrombin accumulation, blocking TNF-alpha and the apoptotic alkaloid staurosporin. At the same time, the cytoprotective effect developed very quickly.
Blood clots appeared in the blood vessels after the introduction of a pro-inflammatory lipopolysaccharide molecule (third row). Preliminary administration of parmodulin-2 (fourth row) leads to normal coagulation, demonstrated in the first row. Source: BIDMC.
In vivo studies on mice have shown that parmodulin-2 reduces the binding of leukocytes and the accumulation of platelets and fibrin during an inflammatory reaction. This confirms the anti-inflammatory and antithrombotic effects of parmodulins demonstrated in in vitro experiments.
The detection of an anti–inflammatory agent that prevents endothelial thrombosis and at the same time preserves the normal state of the blood clotting system is an important step towards effective treatment of inflammatory diseases with minimal side effects. In addition, the work showed the importance of the "organ on a chip" technology for the rapid and safe development and study of drugs that could help patients around the world.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Wyss Institute: Stop the cloths, spare the coagulation.