This has major implications for understanding the molecular basis of sepsis and its treatment

raditionally been two major approaches to drug development for eosinophilic diseases: blocking recruitment of eosinophils into organs and impairing the survival of mature eosinophils. As discussed below, innovative new strategies for future drug development include blocking eosinophil production in the bone marrow and inhibiting eosinophil activation. NIH-PA Author get PR-619 Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Pathogenic actions of eosinophils Eosinophils develop in the bone marrow from hematopoietic stem cells14,15. During human hematopoiesis, common myeloid progenitors give rise to a CD34+IL-5R + eosinophil progenitor14, which is increased in numbers in several diseases including allergies, helminth infections and hypereosinophilic syndrome, suggesting that increased production of eosinophil progenitors is an important checkpoint in disease-associated eosinophilia14,16. Mature human eosinophils contain crystalloid secondary granules, which are primarily composed of highly charged basic proteins, including two major basic proteins, eosinophil cationic protein, eosinophil-derived neurotoxin and eosinophil peroxidase17. Deposition of granules released from eosinophils in tissues is a common finding in eosinophil-associated diseases and likely contributes to disease pathogenesis1822. Major basic protein and eosinophil peroxidase are toxic to a number of different cell types, including airway epithelial cells23,24 and cardiac muscle cells25, and may contribute to tissue damage and organ dysfunction in patients with asthma or hypereosinophilic syndrome. Eosinophil-derived neurotoxin, eosinophil cationic protein belong to the RNase A family of granule proteins that have ribonuclease activity26, are associated with host defense against viruses27 and may have a role in tissue remodeling28. In addition to these cationic proteins, eosinophil granules contain a plethora of preformed cytokines, chemokines, enzymes and growth factors, which results in diverse biological activity for eosinophils in infection and inflammation29. In addition to preformed mediators stored in the granules, eosinophils can release upon activation de novo-synthesized mediators including IL-4, which has the capacity to stimulate adaptive immunity. Current therapies and moving forward Glucocorticoids are the most effective current therapy used to reduce eosinophil numbers in the blood and tissue, but the pleiotropic effects of corticosteroids can result in potentially harmful side effects and limit their therapeutic use. Glucocorticoids promote eosinophil clearance both by directly inducing apoptosis and by inhibiting pro-survival signals induced by cytokines such as IL-3, IL-5 and GM-CSF3032. The tyrosine kinase inhibitor imatinib, the first and only drug approved for hypereosinophilic syndrome, can be an effective treatment to reduce blood eosinophil levels, but only PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19844094 for patients who harbor genetic alterations that involve fusion genes that result in hypereosinophilic syndrome, such as the fusion of the FIP1L1 gene with PDGFRA33,34. Therapy directed against the eosinophil growth factor IL-5 is effective in animal studies35 and has recently been tested in clinical trials; while it results in a substantial decrease in blood eosinophil counts in several different diseases, such as hypereosinophilic syndrome, eosinophilic asthma and eosinophilic esophagitis, the reduction of tissue eosinophilia and improvements in symptoms have been variable depending upon the