Up-regulation of bradykinin receptors in rat bronchia via IκB kinase-mediated inflammatory signaling pathway

Abstract

Thus, IKK inhibition might be a promising approach for treatment of airway inflammation and airway hyperresponsiveness that are often seen in asthmatic patients.

MAPK/NF-κB-dependent upregulation of kinin receptors mediates airway hyperreactivity: A new perspective for the treatment

“…Theoretically, inhibition of the MAPK/NF-B signal mechanisms that mediate upregulation of kinin receptors and subsequent AHR will exert similar therapeutic effects as kinin receptor antagonists. In addition to this, MAPK/NF-B inhibition suppresses not only kinin receptor upregulation and AHR to kinins [8,116,118], but also inhibits inflammatory mediator expression [50,118,120], airway fibroblast [145] and smooth muscle cell proliferation [146][147][148] as well as airway remodeling [149][150][151]. Taken all together, this suggests that inhibition of MAPK/NF-B-dependent kinin receptor upregulation is a better therapeutic strategy than blocking kinin receptors using their antagonists for the treatment of asthmatic and inflammatory airways.…”

“…It is well-known that activation of MAPK subsequently results in phosphorylation (activation) of down-stream transcriptional factor NF-B, which mediates transcription and translation of proinflammatory mediators [117] and de novo synthesis of kinin receptors in airway [8,116,118]. Clinical studies demonstrate that phosphorylated ERK1/2 and p38 MAPK correlate to the airway disease severity in asthma [48,119], suggesting activation of MAPK signaling pathways strongly associates with AHR and asthma exacerbation.…”

“…Upregulation of kinin receptor gene expression by MAPK/NF-B inflammatory signaling pathways may occur at both transcriptional and post-transcriptional levels. Studies have demonstrated that airway smooth muscle cells from individuals with severe asthma show elevated activities of the ERK1/2 and p38 MAPK pathways [119], and the increased contractile responses to kinins can be due to de novo transcription and translation of new kinin receptors in the airway smooth muscle cells via activation of MAPK/NF-B signal pathways [8,43,118]. Theoretically, inhibition of the MAPK/NF-B signal mechanisms that mediate upregulation of kinin receptors and subsequent AHR will exert similar therapeutic effects as kinin receptor antagonists.…”

“…Exposure of murine airways to LPS and/or Poly I:C [39] induces activation of NF-B inflammatory signaling pathway by phosphorylation, ubiquitination and degradation of Ikappa B (IB) that can be inhibited by IB kinase (IKK) inhibitors [120]. Inhibition of IKK by specific IKK inhibitors (BMS-345541, TPCA-1 or MG-132 [39,118] or dexamethasone [38], a non-specific NF-B inhibitor, significantly attenuates kinin receptor upregulation in the airway Nonpeptide antagonists SSR240612 [22,153] WIN64338 [22,155] PS020990 [22] FR173657 [157] Benzodiazepine-based compounds (compound 12) [22] FR184280 [22,155] Dihydroquinoxalinone series (compounds 11 and A) [22] LF16-0687 [22,155] NVPSAA164) [153] MEN16132 [106,155] LF220542 [153] FK3657 [155] Velutinol A [153] Compound 14e [155] 2,3-Diaminopyridine (compounds 6b, 6c and 6f) [153] Bradyzide [22] JSM10292 [158] FR-167344 [157] smooth muscle cells and AHR to kinins. Dexamethasone strongly inhibits overexpression of inflammatory mediators in the airway cells [121] and AHR to kinins [38,116,121].…”

Enhanced airway smooth muscle cell thromboxane receptor signaling via activation of JNK MAPK and extracellular calcium influx

“…Among them, the JNK signaling is demonstrated to tightly regulate the TP receptor related inflammation (Bayat et al, 2008;Kumar et al, 2005) in vasculature and the JNK inhibitor SP600125 exerts effects on allergen-induced airway inflammation and remodeling (Eynott et al, 2004;Nath et al, 2005). A common feature associated with the regulation of airway smooth muscle contraction is a change in intracellular Ca Previously, we have demonstrated that organ culture induced airway hyperresponsiveness to bradykinin occurs via the up-regulated bradykinin receptors (Lei et al, 2010). The present study was designed to investigate if organ culture affects TP receptor mediated airway contractile responses focusing on the roles of transcription and MAPK activity and calcium channel activities.…”