Fight Aging!

Sepsis is a state of runaway inflammation in response to infection, a condition that is more serious and more often fatal in older individuals. With age, the immune system becomes every more overactive and inflammatory, reacting to signals created by the damaged environment of the body. This background of chronic inflammation makes it ever less likely that any given incident of greatly raised inflammatory signaling will successfully resolve. Instead inflammation can rage to the point of causing serious harm and organ failure.

At present, treatments for sepsis are largely palliative, or focus on removing the infectious agent that caused the underlying immune reaction. This can be too little, too late. Sepsis has a high mortality rate. Some present research and development work goes towards sabotaging the feedback loop of runaway inflammatory signaling, such as by delivering cells that will work to resolve inflammation. This seems promising.

Today's open access paper discusses a different approach, however, suppression of oxidative signaling by delivering a natural antioxidant, modified to achieve a greater stability and cell uptake. Oxidative stress, the excessive production of oxidant molecules, goes hand in hand with inflammation in aging tissue, and numerous mechanisms connect oxidative stress to the inflammatory response. It is interesting to see that a suitable antioxidant therapy can make a difference in sepsis.

An Antioxidant Enzyme Therapeutic for Sepsis

Sepsis is a life-threatening organ dysfunction caused by the host's unbalanced response to infection. Septic shock is a type of sepsis in which the changes in metabolism, cells, and hemodynamics significantly increase the likelihood of fatality. Relevant studies have shown that there are more than 19 million sepsis patients worldwide each year, of which 6 million patients die, and the case fatality rate is greater than 25%. About 3 millions of those who survived had cognitive impairments that severely affected their quality of life. Septic shock is also one of the common clinical manifestations of severe patients with COVID-19. People over 65 years of age, infants, immunocompromised patients, and patients with autoimmune diseases, tumors, kidney diseases, and lung diseases are the most susceptible to sepsis. At present, treatments for sepsis mainly include fluid therapy (crystal fluid and albumin), antibacterial drugs, vasoactive drugs (norepinephrine), glucocorticoids, injection immunoglobulin, etc. Due to factors such as individual difference, aging, and antimicrobial resistance, the morbidity and mortality of sepsis remain high.

It has been documented that cytokines and reactive oxygen species (ROS) play essential roles in sepsis. ROS mainly come from cell respiration, protein folding, or various by-products of metabolism. Under pathological conditions, an unbalance of the generation and elimination of ROS results in oxidative stress with excess ROS. Since H2O2 is chemically stable and able to diffuse through cells and tissues, it may accumulate locally or systematically and activate the inflammatory response.

Upon the occurrence of infection, leukocytes are attracted to affected sites and release cytokines and ROS. An excessive level of ROS may damage the biological macromolecules such as DNA, proteins, and lipids, which may cause dysfunction of cells and tissues and further exacerbate the immune response. Uncontrolled production of ROS and cytokines may eventually lead to excessive inflammatory response and cytokine storm. Therefore, eliminating the excessively produced H2O2 helps to reduce the oxidative stress and to regulate the expression of pro-inflammatory cytokines, which is beneficial for the treatment of sepsis.

Organisms can effectively regulate their H2O2 levels through efficient enzymatic reactions. Catalase is the most abundant antioxidant enzyme commonly found in the liver, erythrocytes, and alveolar epithelial cells, and is the most effective catalyst for the decomposition of H2O2. Catalase has attracted much attention in maintaining normal physiological functions and relieving pathological processes. However, exogenous catalase generally exhibits poor in vivo stability and short plasma half-life, which preclude its broad use as therapeutics. Conjugation of therapeutic proteins with poly (ethylene glycol) (PEG) is the golden standard to improve their pharmacokinetics and immunogenicity. Herein, we explore the use of PEG-conjugated catalase as a therapeutic treatment for sepsis. Our results suggest that PEGylated catalase can effectively regulate cytokine production by activated leukocytes, suppress the elevated level of AST, ALT, TNF-α, and IL-6 in mice with induced sepsis, and significantly improve the survival rate of the mice.