Over activated or over abundant neutrophils generate superoxide anion and other reactive oxidants which can create significant oxidative stress and may play a key role in the progression and development of both acute and chronic inflammatory disease. Understanding and eventually blocking the burst of neutrophil activity associated with some inflammatory diseases holds promise as a treatment modality for a number of diseases that are currently poorly managed for patients. One example of such a disease is Acute Respiratory Distress Syndrome (ARDS) characterized by massive infiltration of activated neutrophils into the lungs which impairs gas exchange between the blood and the lungs causing both acute loss of respiratory function and long term damage to the lungs. Blocking the signal transduction cascade leading to neutrophil activation could stop this chain of events and hopefully reduce impact, both acute and chronic, for the patient.
Blocking neutrophil activity requires an understanding of the underlying mechanism and identification of possible points where exogenous regulation could produce the desired ultimate drop in activity. cAMP is an essential second messenger in inflammatory cells and is known to downregulate biological functions in neutrophils. Therefore, increasing cAMP concentrations has the potential to reduce the damage that might otherwise be caused by inflammatory neutrophil burst. Furthermore, activation of protein kinase A (PKA), by cAMP or independent of cAMP concentration, has also been shown to reduce inflammatory response and neutrophil activation. Several plant extracts and other traditional medicine anti-inflammatory formulations have been shown to either directly activate PKA or to inhibit phosphodiesterase 4 (PDE4), the primary enzyme responsible for cAMP hydrolysis in neutrophils and other immune cells. Isolating the active compounds from these traditional medicine anti-inflammatories provides a starting point for the design and development of new drugs – hopefully with greater potency and fewer side effects than those currently in use.
In a recent paper, Tsai et al. examined the mechanism of action for UFM24, a naturally occurring compound found in the seaweed E. flexuosa and in other Asian medicinal plants traditionally used to treat inflammation, and its potential as a treatment for ARDS. In isolated human neutrophils they assessed the effects of UFM24 treatment on a number of enzymes and signal transduction pathways known to be related to neutrophil activation and inflammatory response: superoxide anion formation, intracellular ROS production, elastase release, lactate dehydrogenase activity, NADPH oxidase activity, intracellular cAMP concentrations, PKA activity (Arbor Assays PKA Colorimetric Activity Kit, Cat.# K027-H1), PDE activity, adenylate cyclase activity, CD11b express, intracellular calcium concentration, and AKT phosphorylation. Their studies showed the anti-inflammatory effects can be attributed to several different actions of the compound including, most significantly, the direct and selective inhibition of PDE4, and the activation of PKA. Tsai et al also used a mouse model of acute lung injury to demonstrate treatment with UFM24 (delivered intraperitoneally) significantly reduced lung injury induced by lipopolysaccharide (LPS), showing the effects observed during in vitro studies carry over into in vivo application; proving that UFM24, or related compounds, have potential as alternative treatments for neutrophil-mediated acute lung injury whether caused by acute or chronic disease.
Overall improvements in the treatment of inflammatory response could be beneficial to patients suffering with a wide range of inflammation-mediated diseases. Full understanding of the mechansims through which these treatments act is key to the ability to choose the most appropriate intervention for each situation.