Inflammation is a defense mechanism of the body to protect it from infection and injury.  The inflammatory response is started by white blood cells releasing defense molecules to remove injurious stimuli such as damaged cells, pathogens or irritants.

Redness, pain, swelling, heat and loss of function in the injured tissue can all result from the inflammatory response. If the inflammatory reaction becomes uncontrolled, tissue damage can occur. The inflammation response can be short-lived (acute inflammation) or long-lived (chronic inflammation). Chronic inflammation can result in amplification of tissue damage and result in chronic diseases such as asthma, chronic obstructive pulmonary disease (COPD), rhinitis, atherosclerosis, psoriasis and arthritis.

Bioactive lipids are involved in most of the metabolic pathways that mediate inflammation. In many diseases, a significant part of the inflammatory response is the biosynthesis of eicosanoids by white blood cells. Eicosanoids are bioactive lipid molecules derived from the polyunsaturated fatty acid, arachidonic acid. In addition to the several major eicosanoid metabolism pathways in the body, there are numerous other pathways involving bioactive lipids that affect not only inflammation but also cancer, cardiovascular disease and metabolic diseases.

Bioactive lipids

Bioactive lipids, including eicosanoids and phospholipids, are produced in cells in response to external stimuli and their interaction with specific receptors activates intracellular signaling pathways that can contribute to multiple cellular processes. Bioactive lipids have different physiological or pathological outcomes depending on the overall context of the stimulation. Lipid metabolizing enzymes and receptors of these bioactive lipids have been targeted for drug development at Amira. The scientific team at Amira has been successful in identifying multiple small molecule drug candidates for protein targets in these bioactive lipid pathways. To date, Amira’s research has primarily focused on bioactive lipids involved in the leukotriene, prostaglandin and lysophosphatidic acid pathways.

Leukotrienes (LTs)

LTs, together with prostaglandins (PGs) are the major constituents of a group of biologically active oxygenated fatty acids known as eicosanoids. Unlike many other biologically active molecules, the eicosanoids are not stored as preformed components of the immune reponse within their secreting cells but are synthesized de novo from membrane phospholipids through a cascade of enzymes known as the arachidonic acid cascade, named after the common precursor molecule of all eicosanoids. LTs play a major role in the inflamatory response to injury: they have been implicated in the pathogenesis of several inflammatory diseases, most notably asthma, COPD, allergic rhinitis and atherosclerosis. The role of LTs as inflammatory mediators of disease has made their receptors attractive therapeutic targets.

Prostaglandins (PGs)

As with LTs, PGs are derived from arachidonic acid. PGs are highly potent substances and are made on demand by cell membranes in virtually every body tissue. They participate in the transmission of nerve impulses, the body's defenses against infection, regulate the rate of metabolism in various tissues and play a major role in the inflammatory response. PGD₂ is the major prostanoid produced by mast cells and it has been detected in high concentrations in the airways of asthmatics after antigen challenge. It has become evident that the effect of PGD₂ is through the DP2 receptor (also known as CRTH2, chemoattractant receptor expressed on Th2 cells). Therefore, DP2 is an attractive target to suppress airway inflammation and, consequently, to improve lung function in asthma and COPD.

Lysophosphatidic acid (LPA)

LPA is a bioactive phospholipid with diverse physiological actions on many cell types. Its concentrations are elevated in affected tissues in diseases, including in the bronchoalveolar lavage fluid (BALF) from idiopathic pulmonory fibrosis (IPF) patients. LPA levels are also increased in BALF following lung injury in a bleomycin murine model of pulmonary fibrosis. Mice lacking one of the LPA receptors, namely LPA1, are markedly protected from fibrosis in this model. Therefore, the LPA1 receptor is a compelling target for the potential treatment of IPF.