1. Discovery and development of Ulinastatin
Ulinastatin is a urine-derived serine protease inhibitor, with the trade name of UTI, used as a broad-spectrum anti-inflammatory agent to treat many different disorders. Ulinastatin was first discovered in 1962 from the urine of healthy men by a Japanese researcher named Dr. Kiyoshi Kasahara. Dr. Kasahara observed that the urine of healthy individuals contains a protein that can prevent the activation of trypsin, a digestive enzyme that can cause damage to the pancreas if it is activated prematurely. From there, researchers discovered that this protein, later named Ulinastatin, has anti-inflammatory and antiprotease properties that make it suitable for treating various diseases. In the 1970s, a Japanese company, Tanabe Seiyaku, began development of ulinastatin derived from human urine and launched the product in 1990. Since then, Ulinastatin has been used as a treatment for various medical conditions like sepsis, acute pancreatitis, inflammation-induced damage in the liver and kidneys, inflammatory bowel disease, and many others.
Currently, UTI is produced in large quantities by recombinant DNA technology using bacterial fermentation systems and is approved for clinical use in Japan, China, and many other countries. The further development and clinical trial of UTI are still ongoing to discover new applications and understand its mechanism of action in treating complex medical disorders.
2. Structure and function of UTI
Ulinastatin is a glycoprotein with a molecular weight of about 67 kDa. It consists of 573 amino acids and contains three homologous domains that have a similar structure to serine protease inhibitors. The structure of ulinastatin has a hairpin loop, which contains a reactive site that is capable of binding to proteolytic enzymes. This loop is responsible for ulinastatin's mechanism of action as a protease inhibitor. UTI functions as an anti-inflammatory agent, primarily inhibiting the activity of trypsin, chymotrypsin, and elastase proteases, all of which are involved in inflammatory reactions. UTI also has other functions such as blocking the production of inflammatory cytokines, scavenging reactive oxygen species, modulating the complement system, and restoring endothelial cell barrier function.
UTI's anti-inflammatory properties are attributed to its ability to inhibit the activity of various proteases involved in the inflammatory process. For example, in sepsis, UTI inhibits the production of pro-inflammatory cytokines such as TNF-α and IL-6, by inhibiting proteases that activate these cytokines. In acute pancreatitis, UTI inhibits pancreatic enzymes such as trypsin, which are released when the pancreas is damaged, thereby preventing further inflammation and damage to the pancreas. UTI also has organ-protective effects in liver and kidney inflammation, where it prevents the activation of proteases that cause tissue damage. In addition, UTI has been shown to inhibit the production of oxygen-free radicals, which contribute to tissue damage and inflammation.
3. Medical effect of UTI
Ulinastatin has several medical effects due to its anti-inflammatory and organ-protective properties. Some of the medical conditions in which UTI has been studied and found to be effective are as follows:
- Sepsis: UTI has been shown to improve outcomes in patients with sepsis by reducing inflammation and preventing organ damage. It inhibits the production of pro-inflammatory cytokines and reduces the activation of neutrophils, preventing the release of reactive oxygen species.
- Acute pancreatitis: UTI has been found to be effective in reducing the severity of acute pancreatitis by inhibiting pancreatic enzymes such as trypsin. This helps to prevent further inflammation and damage to the pancreas.
- Trauma: UTI has been shown to have a protective effect in trauma-induced organ damage. It reduces the activation of neutrophils and prevents the release of reactive oxygen species, thereby preventing tissue damage and inflammation.
- Cardiovascular diseases: UTI has been found to be effective in reducing the risk of cardiovascular diseases such as myocardial infarction and stroke. It improves endothelial function, inhibits the production of pro-inflammatory cytokines, and reduces the formation of blood clots.
- Kidney disease: UTI has been shown to have a protective effect in kidney diseases such as acute kidney injury and chronic kidney disease. It reduces inflammation and oxidative stress, preventing further damage to the kidneys.
Overall, UTI has been studied extensively and found to have beneficial effects in several medical conditions. Its mechanism of action in inhibiting proteases and reducing inflammation makes it a promising candidate for the treatment of various inflammatory disorders.
