Allergen‐induced inflammation and airway epithelial and smooth muscle cell proliferation: role of Jun N‐terminal kinase

Abstract

1 Chronic cellular inflammation and airway wall remodelling with subepithelial fibrosis and airway smooth muscle (ASM) cell hyperplasia are features of chronic asthma. Jun N-terminal kinase (JNK) may be implicated in these processes by regulating the transcriptional activity of activator protein (AP)-1. 2 We examined the effects of an inhibitor of JNK, SP600125 (anthra [1,9-cd] pyrazole-6 (2 H)-one), in a model of chronic allergic inflammation in the rat. 3 Rats sensitised to ovalbumin (OA) were exposed to OA-aerosol every third day on six occasions and were treated with SP600125 (30 mg kg À1 b.i.d; 360 mg in total) for 12 days, starting after the second through to the sixth OA exposure. We measured eosinophilic and T-cell inflammation in the airways, proliferation of ASM cells and epithelial cells by incorporation of bromodeoxyuridine (BrdU), and bronchial responsiveness to acetylcholine. 4 SP600125 significantly reduced the number of eosinophils (Po0.05) and lymphocytes (Po0.05) in bronchoalveolar lavage fluid, suppressed eosinophilic (Po0.05) and CD 2 þ T-cell (Po0.05) infiltration within the bronchial submucosa, and the increased DNA incorporation in ASM (Po0.05) and epithelial cell incorporation (Po0.05). 5 SP600125 did not alter bronchial hyper-responsiveness observed after chronic allergen exposure. 6 Pathways regulated by JNK positively regulate ASM cell proliferation and allergic cellular inflammation following chronic allergen exposure.

c-Jun N-terminal kinase-dependent mechanisms in respiratory disease

“…SP600125 activity has been reported in a number of rodent models of pulmonary disease, including single and chronic allergen challenge in the rat [45,46] and mouse [47], and bleomycin-induced injury and repair in the mouse [48]. Some of these studies have been repeated and confirmed using proprietary JNK inhibitors from a distinct chemical class, a JNK inhibitor from a discovery programme at Serono [49,50] and AP-1 activation inhibitors [51].…”

“…A novel observation in chronically allergen-challenged rats and mice was that JNK inhibitor caused significant inhibition of both airway smooth muscle proliferation and goblet cell hyperplasia, which are common features of the asthmatic airway [46,47]. It remains unclear whether this effect of JNK inhibitor was due to inhibition of growth factor expression or via direct inhibition of cell cycle mechanisms.…”

c-Jun N-terminal kinase mediates constitutive human eosinophil apoptosis

“…[30][31][32] Interestingly, the numbers of eosinophils in the bronchial tissue were not reduced after pre-treatment with SP600125. [32] Our present result that inhibition of JNK activity does not increase but rather decreases apoptosis of eosinophils is in line with the inability of SP600125 to reduce tissue eosinophilia.…”

“…[32] Our present result that inhibition of JNK activity does not increase but rather decreases apoptosis of eosinophils is in line with the inability of SP600125 to reduce tissue eosinophilia. However, SP600125 reduces the production of several cytokines and chemokines [30][31][32] as well as inhibits several other kinases [28] and thus the net effect of SP600125 on pulmonary inflammatory indices is a result of a combination of all its effects.…”

c-Jun NH2-Terminal Kinase Is Crucially Involved in Renal Tubulo-Interstitial Inflammation

“…MAP kinases modulate gene transcription, mainly through activation of transcription factors. In particular, the MAP kinase c-Jun NH 2 -terminal kinase (JNK) and its downstream transcription factor c-Jun have been associated with inflammation, for example, in colitis (Assi et al, 2006), asthma (Eynott et al, 2003), and arthritis (Han et al, 2001). Moreover, glomerular JNK activation has been demonstrated in experimental glomerulonephritis (Seto et al, 1998).…”