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

Abstract

Airway hyperreactivity (AHR) is a major feature of asthmatic and inflammatory airways. Cigarette smoke exposure, and bacterial and viral infections are well-known environmental risk factors for AHR, but knowledge about the underlying molecular mechanisms on how these risk factors lead to the development of AHR is limited. Activation of intracellular mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB) and their related signal pathways including protein kinase C (PKC), phosphoinositide 3-kinase (PI3K) and protein kinase A (PKA) signaling pathways may result in airway kinin receptor upregulation, which is suggested to play an important role in the development of AHR. Environmental risk factors trigger the production of pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α) and interleukins (ILs) that activate intracellular MAPK- and NF-κB-dependent inflammatory pathways, which subsequently lead to AHR via kinin receptor upregulation. Blockage of intracellular MAPK/NF-κB signaling prevents kinin B₁ and B₂ receptor expression in the airways, resulting in a decrease in the response to bradykinin (kinin B₂ receptor agonist) and des-Arg⁹-bradykinin (kinin B₁ receptor agonist). This suggests that MAPK- and NF-κB-dependent kinin receptor upregulation can provide a novel option for treatment of AHR in asthmatic as well as in other inflammatory airway diseases.

Introduction

Airway hyperreactivity (AHR), inflammation and remodeling with functional abnormalities and structural alterations in the airways are major features of asthmatic and inflammatory airways [1], [2]. Environmental risk factors for AHR such as exposure to cigarette smoke [3], [4], and bacterial [5] or viral infection [6], [7] may lead to airway inflammation, which triggers production of pro-inflammatory mediators like tumor necrosis factor-α (TNF-α), interleukins (ILs) and kinins. These pro-inflammatory mediators can result in activation of intracellular mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB) signal pathways that induce airway G-protein coupled receptor (GPCR) upregulation for kinins [8], [9], [10] and airway epithelium dysfunction [6], [11]. Subsequently, the kinin receptor upregulation and the epithelium dysfunction result in AHR that are often seen in asthmatic and inflammatory airways.

Bradykinin, TNF-α, ILs and growth factors may induce activation of MAPK/NF-κB and their related signal pathways including protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K) [12], [13]. In addition, the NF-κB pathways can also be activated by protein kinase A (PKA) signaling [14]. The activation of MAPK/NF-κB and their related signal pathways stimulates airway cell proliferation and production of cytokines [12], [13], airway remodeling [15], [16], mucin gene expression and mucin secretion [17]. The production of pro-inflammatory mediators like IL-6 and IL-8 induced by bradykinin [13] may enhance the MAPK/NF-κB signaling and further induce airway kinin receptor upregulation as well. Interestingly, in the lung fibroblast cell line IMR-90, binding of bradykinin to B₂ receptor triggers downregulation of receptor surface expression, while bradykinin induces upregulation of the receptor in human bronchial epithelial cell line BEAS2B [18]. The upregulation of kinin B₂ receptors is most likely through bradykinin-induced inflammatory signal mechanisms.

Bradykinin and related kinins are pro-inflammatory mediators [19]. Mainly, there are four functional kinin peptides; des-Arg⁹-bradykinin and des-Arg¹⁰-kallidin (equipotent agonists at kinin B₁ receptor), and bradykinin and kallidin (selective kinin B₂ receptor agonists) [20]. The expression of kinin B₁ receptors is induced under inflammatory stimuli, while the kinin B₂ receptor is constitutively expressed [21]. Both kinin B₁ and B₂ receptors belong to the large family of GPCR and mediate airway inflammation and AHR in asthmatic and inflammatory airways [22]. In healthy humans, inhalation of bradykinin has little or no effect, but in asthmatics, it produces strong bronchoconstriction [23], and more importantly, asthmatic subjects show a greater degree of AHR to bradykinin than to methacholine after allergen challenge [24].

The kinins exert pharmacological effects through the kinin B₁ and B₂ receptors [22], [25]. Gram-negative bacteria produce endotoxin (Lipopolysaccharide, LPS) that induces acute lung injury via activation of kinin B₁ receptors [26], and blockage of kinin B₁ receptor by its antagonist R954 inhibits eosinophil activation and proliferation in murine asthma [27]. Through kinin B₂ receptors, bradykinin induces increased expression of the pro-inflammatory mediator IL-6 [28]. In human epithelial cells, the kinin B₂ receptor mediates inflammatory signaling through activation of NF-κB and increase in cyclooxygenase-2 (COX₂) expression [29]. On the other hand, there are elevated levels of kinin receptor agonist bradykinin [30], pro-inflammatory mediator IL-8 and human tissue kallikrein activation in bronchoalveolar lavage fluids from allergic subjects and asthmatic patients with rhinovirus infection [31].

Kinins are involved in the development of allergic nasal hyperresponsiveness in guinea pigs through activation of not only kinin B₂, but also kinin B₁ receptors [32]. Sensitized Brown Norway rats exhibit AHR to bradykinin induced by allergen challenge [33]. Aerosol NPC-567, the kinin B₂ receptor antagonist, given before, during and 4 h after antigen challenge significantly inhibits the late bronchial response to the antigen challenge [34]. Ovalbumin-sensitized guinea pigs display AHR to bradykinin and histamine. These responses can be attenuated by the kinin B₂ receptor antagonist MEN16132 [7]. In the human nasal airway, bradykinin receptors mediate nasal blockage and plasma extravasation induced by either bradykinin or antigen challenge [35]. Allergic rhinitis subjects display significantly higher expression of kinin B₁ receptor mRNA than normal subjects, and nasal allergen challenge increases kinin B₁ receptor mRNA expression in allergic rhinitis subjects [36]. In addition to this, kinin B₁ receptor antagonist R954 inhibits eosinophil activation, proliferation and migration in a murine model of asthma [27]. Interestingly, allergen-induced hyperresponsiveness to bradykinin is more pronounced than that to methacholine in asthmatic patients [24], [37]. These in vivo data suggest that kinin receptor upregulation is most likely a promising therapeutic target for the treatment of AHR. In agreement with this, dexamethasone, a well-known anti-airway inflammation drug, inhibits kinin receptor upregulation and AHR to kinins in murine airway in vitro [38], [39], and suppresses sidestream cigarette smoke exposure-induced AHR and airway inflammation in vivo in mice [40]. In clinical studies, corticosteroids decrease the kinin receptor expression and improve the symptoms of asthmatic patients [37], [41], [42].

The expression of kinin B₁ and/or B₂ receptors can be upregulated in AHR [43], during airway inflammation [7] and infection [44]. In addition, bradykinin may upregulate the expression of Toll-like receptor 4 (TLR4) and promotes an additive increase in inflammatory responses to lipopolysaccharides (endotoxin) [45]. Investigations of intracellular molecular signal mechanisms show that activation of MAPK/NF-κB signal pathways regulate cellular events like differentiation, proliferation, apoptosis and production of pro-inflammatory mediators as well as expression of GPCR in airways [40], [46], [47]. In asthmatic subjects, there are significant levels of phosphorylated extracellular signal regulated kinases 1 and 2 (ERK1/2) and p38 MAPK that correlate to the severity of airway disease [48], [49], suggesting that inhibition of MAPK signal pathways could be a new strategy for treatment of asthma and airway inflammation [50], [51]. We have demonstrated a link between pro-inflammatory mediators and AHR, i.e. the environmental risk factors via activation of intracellular MAPK/NF-κB signal transduction pathways upregulate kinin receptor expressions in the airways, subsequently resulting in AHR [8], [39], [43]. Recent studies show that inhibition of p38 MAPK reverses steroid insensitivity in severe asthma [52], and the MAPK inhibitor and corticosteroid have a synergistic effect on inhibiting LPS-mediated cytokine production by alveolar macrophages from patients with chronic airway disease [53]. This review updates knowledge about emerging role of MAPK/NF-κB-dependent kinin receptor upregulation in the development of AHR, and suggests a new perspective for the treatment of AHR in asthma and airway inflammation.