Hydrogen Sulfide in Inflammation

     Sepsis is the pathological presence of an infection in the blood or other tissue; it is commonly caused by bacterial infection and can lead to multiple organ failure and ultimately death. This area is of ever increasing importance as more and more cases of antibiotic resistance infections occur. However, in many cases it is not the infection that directly kills the patient; it is an uncontrolled overreaction by the immune system. This pathological immune system response is referred to as systemic inflammatory response syndrome (SIRS) and is characterized by hypotension, tachycardia and a higher or lower body temperature. SIRS can result in multi-organ failure, particularly damage to the lungs with acute respiratory distress syndrome. Our research aims to develop effective techniques for quickly diagnosing sepsis and SIRS using novel biomarkers, as well as developing new treatments using a combination of cellular models of the disease and clinical samples from sepsis sufferers.

     The immune system’s response to infection and toxins is a normal and crucial function of human physiology. Upon recognition of an infection or toxin, immune cells produce a range of signaling molecules including cytokines and chemokines to further recruit and activate immune cells. However, the immune system can produce cytokines and chemokines at cytotoxic levels, as well as other cytotoxic compounds such as reactive oxygen species (ROS) including free radicals and reactive nitrogen species (RNS) such as nitric oxide.  In sepsis induced systemic inflammatory response syndrome (SIRS), the cytotoxic compounds can reach dangerous levels in the blood, causing damage to sensitive organs such as the lungs and the kidneys. The downstream effects of this organ damage, such as hypotension and respiratory failure, can result in further organ failure and death. Two molecules that may be crucial in this pathological activation of immune cells are hydrogen sulfide and substance P.

      Hydrogen sulfide is a novel gaseous signaling molecule, at normal physiological levels it is crucial in many processes ranging from memory and learning to vasodilatation.  It is produced at high levels during inflammation, this signals the recruitment and activation of immune cells. Hydrogen sulfide is produced through the removal of the thiol group of L-cysteine by the enzymes cystathionine γ lyase (CSE) systemically or cystathionine β synthase (CBS) in the central nervous system. The exact mechanisms of how hydrogen sulfide elicits its effects are still being elucidated, however, it is clear that it involves the modulation of cellular function through MAP/ERK signaling pathways, vanilloid receptor pathways, and possibly through altering cellular glutathione oxidation states. Animal models of sepsis have shown that reducing the levels of hydrogen sulfide production by administering CSE enzyme inhibitors, improved the animals’ condition and increased survival rates.

      Substance P is a small peptide that is a signaling molecule involved in inflammation and pain. It is produced by afferent somatic sensory neurons and activated macrophages and causes an increase in immune cell activation, vasodialation and pain signaling. Substance P acts, at least in part, through binding to the neurokinin 1 (NK-1) receptor causing cellular changes through the MAP/ERK pathways to illicit its effects.  Nk-1 antagonists have been shown in animal models of sepsis to be protective of lung injury, demonstrating the importance of substance P in sepsis induced SIRS.

      Because hydrogen sulfide and substance P are involved in pathological immune cell activation, there is potential for them to be used as biomarkers of sepsis and sepsis induced SIRS. They are also an attractive potential target of pharmacological intervention for the treatment of inflammatory diseases such as SIRS.

11. November 2011 by jackrrivers
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