c-Jun N-terminal kinase-dependent mechanisms in respiratory disease.
Respiratory diseases pose a multifaceted dilemma. Although the symptoms and pathology are obvious and provide multiple opportunities for therapeutic investigation, at the same time, the molecular complexities and prioritisation are overwhelming. Even within a disease such as asthma, the number of inducers, cell types, secondary mediators, chemical changes, immune responses and tissue modifications is remarkable. One means of therapeutically targeting this complexity is to identify individual factors responsible for regulating multiple disease processes. The mitogen-activated protein kinase family integrates multiple diverse stimuli, and, in turn, initiates a cell response by phosphorylating and thereby modulating the activity of many target proteins. The c-Jun N-terminal kinase is a critical regulator of pro-inflammatory genes, tissue remodelling and apoptosis, and, therefore, represents an attractive target for novel therapies. Pre-clinical and clinical investigation into the efficacy of c-Jun N-terminal kinase inhibitors has been ongoing since the late 1990s. Over the course of this work, hypotheses have shifted as to the role of c-Jun N-terminal kinase in the many processes that promote allergic, inflammatory, obstructive and fibrotic diseases of the lung. Inhibition of c-Jun N-terminal kinase may indeed provide a means of suppressing more pathological mechanisms in respiratory disease than first suspected.
Bennett
B L
BL
Experimental Therapeutics-Inflammation, Celgene, San Diego, CA 92121, USA. bbennett@celgene.com
D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012120:Respiration Disorders / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics
D005938:Glucocorticoids; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases