CXCR2 antagonists for the treatment of pulmonary disease.
Chemokines have long been implicated in the initiation and amplification of inflammatory responses by virtue of their role in leukocyte chemotaxis. The expression of one of the receptors for these chemokines, CXCR2, on a variety of cell types and tissues suggests that these receptors may have a broad functional role under both constitutive conditions and in the pathophysiology of a number of acute and chronic diseases. With the development of several pharmacological, immunological and genetic tools to study CXCR2 function, an important role for this CXC chemokine receptor subtype has been identified in chronic obstructive pulmonary disease (COPD), asthma and fibrotic pulmonary disorders. Interference with CXCR2 receptor function has demonstrated different effects in the lungs including inhibition of pulmonary damage induced by neutrophils (PMNs), antigen or irritant-induced goblet cell hyperplasia and angiogenesis/collagen deposition caused by lung injury. Many of these features are common to inflammatory and fibrotic disorders of the lung. Clinical trials evaluating small molecule CXCR2 antagonists in COPD, asthma and cystic fibrosis are currently underway. These studies hold considerable promise for identifying novel and efficacious treatments of pulmonary disorders.
Chapman
R W
RW
Schering-Plough Research Institute, Kenilworth, New Jersey 08844, USA. richard.chapman@spcorp.com
Phillips
J E
JE
Hipkin
R W
RW
Curran
A K
AK
Lundell
D
D
Fine
J S
JS
D000818:Animals; D019743:Chemokines, CXC / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D055808:Drug Discovery; D006801:Humans; D008171:Lung Diseases / Q000188:drug therapy* / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D019743:Chemokines, CXC; D023063:Receptors, Interleukin-8B