Mechanisms of asthma and allergic inflammationCysteinyl leukotrienes synergize with growth factors to induce proliferation of human bronchial fibroblasts
Section snippets
Cell cultures
Primary human bronchial fibroblasts were grown from bronchial biopsy specimens obtained from healthy subjects, as previously reported.16 The detailed methods are described in the Methods section in the Online Repository at www.jacionline.org.
Reagents
LTD4, LTC4, and MK-571 were from Cayman Chemical (Ann Arbor, Mich). Montelukast sodium was a kind gift from Dr Jilly Evans (Merck, West Point, Pa). Other reagents are described in the Methods section in the Online Repository at www.jacionline.org.
Mitogenesis analyses
Bronchial
LTD4 synergizes with EGF to induce mitogenesis
To assess whether cys-LTs have mitogenic activity, we analyzed the incorporation of tritiated thymidine into primary cultures of bronchial fibroblasts. LTC4 or LTD4 alone had little mitogenic effect. However, when coincubated with EGF, both LTC4 and LTD4 dose-dependently augmented EGF-induced mitogenesis. Thus 0.5 μmol/L of LTD4 or LTC4 increased mitogenesis by 408% ± 93% (P = .002) or 421% ± 97% (P = .002), respectively, compared with EGF (1 ng/mL) alone. The dose-response curves show very
Discussion
Airway remodeling is an important component of chronic asthma involving proliferation and activation of airway fibroblasts.20 Previous studies have shown that LTC4 and LTD4 stimulate mitogenesis of human skin fibroblasts in vitro.21 Furthermore, targeted deletion of the CysLT1R gene unexpectedly augmented bleomycin-induced lung fibrosis and alveolar septal thickening,22 whereas deletion of CysLT2R prevented these effects.23 These data suggest that CysLT1R and CysLT2R have distinct functions
References (33)
- et al.
Role of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling
J Allergy Clin Immunol
(2003) - et al.
Characterization of the human cysteinyl leukotriene 2 receptor
J Biol Chem
(2000) - et al.
CysLT1 receptor upregulation by TGF-β and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4
J Allergy Clin Immunol
(2003) - et al.
Epithelial-mesenchymal interactions in the pathogenesis of asthma
J Allergy Clin Immunol
(2000) - et al.
Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice
J Biol Chem
(2004) - et al.
PPADS, a novel functionally selective antagonist of P2 purinoceptor-mediated responses
Eur J Pharmacol
(1992) - et al.
Antagonistic resistant contractions of the porcine pulmonary artery by cysteinyl-leukotrienes
Eur J Pharmacol
(2000) - et al.
Leukotriene D4 stimulates collagen production from myofibroblast transformed by TGF-β
J Allergy Clin Immunol
(2004) - et al.
Characterization of the human cysteinyl leukotriene CysLT1 receptor
Nature
(1999) - et al.
Molecular cloning and characterization of a second human cysteinyl leukotriene receptor: discovery of a subtype selective agonist
Mol Pharmacol
(2000)
Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial
Eur Respir J
A role of for cysteinyl leukotrienes in airway remodeling in a mouse asthma model
Am J Respir Crit Care Med
The effect of pranlukast on allergen-induced bone marrow eosinophilopoiesis in subjects with asthma
Am J Respir Crit Care Med
The Zafirlukast Study Group. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids
Am J Respir Crit Care Med
Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients
BMJ
Involvement of cysteinyl leukotrienes in airway smooth muscle cell DNA synthesis after repeated allergen exposure in sensitized Brown Norway rats
Br J Pharmacol
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Leukotriene D<inf>4</inf> role in allergic asthma pathogenesis from cellular and therapeutic perspectives
2020, Life SciencesCitation Excerpt :Fibroblasts located in the peripheral airways express higher levels of CysLT1R compared to the one in the central airways, and these expression level doesn't differ between asthmatics and non-asthmatics [106]. Although LTD4 alone doesn't have an effect on primary human bronchial fibroblasts proliferation, it can synergize with other growth factors including EGF, PDGF, and FGF to potentiate cell proliferation through a PKC-mediated intracellular pathway, leading to a sustained growth factor-dependent phosphorylation of Erk-1/2 and Akt [107]. LTD4 potentiates the TGFβ1-mediated secretion of collagen in human fetal lung fibroblasts.
Lipid mediator Leukotriene D<inf>4</inf>-induces airway epithelial cells proliferation through EGFR/ERK1/2 pathway
2018, Prostaglandins and Other Lipid MediatorsCitation Excerpt :Studies have suggested that GPCRs such as CysLT receptors require growth factor receptors and their tyrosine kinase activity to induce mitogenic effects [9,18]. The CysLT receptors have broader capacity to synergize with other receptor tyrosine kinases (RTKs) and not necessarily transactivate EGFR [10]. We also found that LTD4 caused EGFR phosphorylation concentration-dependently in SAECs and A549 cells which was increased by EGF, though non-significantly, suggesting that the effect of two stimulants could be mediated through EGFR activation (Fig. 4A & B and D & E, respectively), which leads to increased ERK1/2 phosphorylation and activation.
The epidermal growth factor receptor inhibitor AG1478 inhibits eosinophilic inflammation in upper airways
2018, Clinical ImmunologyCitation Excerpt :Ligand-shedding dependent transactivation of the EGFR is mediated by ligands such as amphiregulin and TGF-α, which are cleaved from their membrane-anchored forms by activated metalloproteinase. Although important roles of EGFR signaling have been reported in bronchial and alveolar fibroblasts [33,34], this is the first report to show inhibitory effects of the EGFR inhibitor AG1478 on cytokine secretion from nasal fibroblasts. Mucus hypersecretion and eosinophil infiltration are common characteristics of allergic airway inflammation [3].
Bradykinin-induced asthmatic fibroblast/myofibroblast activities via bradykinin B<inf>2</inf> receptor and different MAPK pathways
2013, European Journal of PharmacologyCitation Excerpt :In some experiments, cells were pre-incubated with bradykinin B2 receptor antagonist HOE140 (1 μM; 15 min; Sigma-Aldrich) before exposure to bradykinin. The signaling pathways involved in bradykinin-induced HABFb and HNBFb functions were investigated using the specific inhibitors (1 h pretreatment): U0126 (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene) at 10 µM (for ERK1/2; Sigma-Aldrich) (Davies et al., 2000; Kuang et al., 2007), SB203580 (4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine) at 10 µM (for p38 MAPK; Sigma-Aldrich) (Davies et al., 2000; Han et al., 2009), AG1478 (N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinanine) at 1 µM (for EGF receptor; Sigma-Aldrich) (Puri et al., 2008; Tsukagoshi et al., 2002), and GM6001 (N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-l-tryptofan methylamine) at 20 µM (for metalloproteinases; Inalco S.p.A, Milan, Italy) (Devel et al., 2012; Yoshisue et al., 2007). ERK1/2 and p38 activation were evaluated in fibroblasts stimulated with bradykinin (10−11 or 10−6 M) for 5 min.
Effects of montelukast on subepithelial/peribronchial fibrosis in a murine model of ovalbumin induced chronic asthma
2013, International ImmunopharmacologyCysteinyl leukotrienes regulate TGF-Β<inf>1</inf> and collagen production by bronchial fibroblasts obtained from asthmatic subjects
2012, Prostaglandins Leukotrienes and Essential Fatty Acids
Supported by Asthma UK.
Disclosure of potential conflict of interest: H. Yoshisue and D. E. Davies have received grant support from Asthma UK. A. P. Sampson has consultant arrangements with Merck Sharp & Dohme; has received grant support from Merck & Co, Ono Pharma UK Ltd, and AstraZeneca; and has received honoraria from Merck & Co. The rest of the authors have declared that they have no conflict of interest.