Leukotriene E4 and granulocytic infiltration into asthmatic airways

Laitinen, Lauri A.; Haahtela, Tari; Vilkka, Vesa; Lee, T.H; Spur, Bernd W.

doi:10.1016/0140-6736(93)91073-u

Cited by 486 publications

(287 citation statements)

References 7 publications

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“…In contrast, pretreatment with LTE 4 , but not LTC 4 or LTD 4 , enhanced the response of guinea pig trachea (9) or human bronchial smooth muscle to histamine (10). Furthermore, in limited studies, LTE 4 was comparable with LTC 4 or LTD 4 in eliciting a vascular leak in skin in guinea pigs (11) or humans (12), and inhalation of LTE 4 , but not LTD 4 , by patients with asthma elicited an accumulation of eosinophils and basophils into the bronchial mucosa (13,14). These observations strongly supported an agonist function for LTE 4 , likely mediated by a receptor separate from those that are activated by its short-lived precursors (15).…”

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confidence: 99%

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Kanaoka

Maekawa

Austen

2013

Journal of Biological Chemistry

159

154

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Background: A most stable cysteinyl leukotriene, LTE 4 , mediates vascular permeability in mice lacking the two known receptors. Results: GPR99 deficiency abolishes LTE 4 -induced vascular permeability in mice also lacking the two known receptors. Conclusion: GPR99 is a potential third cysteinyl leukotriene receptor. Significance: GPR99 may be a therapeutic target for inflammatory diseases.The cysteinyl leukotrienes (cys-LTs), leukotriene C 4 (LTC 4 ), a conjugation product of glutathione and eicosatetraenoic acid, and its metabolites, LTD 4 and LTE 4 , are lipid mediators of smooth muscle constriction and inflammation in asthma. LTD 4 is the most potent ligand for the type 1 cys-LT receptor (CysLT 1 R), and LTC 4 and LTD 4 have similar lesser potency for CysLT 2 R, whereas LTE 4 has little potency for either receptor. Cysltr1/Cysltr2 ؊/؊ mice, lacking the two defined receptors, exhibited a comparable dose-dependent vascular leak to intradermal injection of LTC 4 or LTD 4 and an augmented response to LTE 4 as compared with WT mice. As LTE 4 retains a cysteine residue and might provide recognition via a dicarboxylic acid structure, we screened cDNAs within the P2Y nucleotide receptor family containing CysLTRs and dicarboxylic acid receptors with trans-activator reporter gene assays. GPR99, previously described as an oxoglutarate receptor (Oxgr1), showed both a functional and a binding response to LTE 4 in these transfectants. We generated Gpr99 ؊/؊ and Gpr99/Cysltr1/Cysltr2 ؊/؊ mice for comparison with WT and Cysltr1/Cysltr2 ؊/؊ mice. Strikingly, GPR99 deficiency in the Cysltr1/Cysltr2 ؊/؊ mice virtually eliminated the vascular leak in response to the cys-LT ligands, indicating GPR99 as a potential CysLT 3 R active in the Cysltr1/Cysltr2 ؊/؊ mice. Importantly, the Gpr99 ؊/؊ mice showed a dose-dependent loss of LTE 4 -mediated vascular permeability, but not to LTC 4 or LTD 4 , revealing a preference of GPR99 for LTE 4 even when CysLT 1 R is present. As LTE 4 is the predominant cys-LT species in inflamed tissues, GPR99 may provide a new therapeutic target.Leukotriene C 4 (LTC 4 ), 2 LTD 4 , and LTE 4 , collectively called cysteinyl leukotrienes (cys-LTs), are proinflammatory mediators derived from arachidonic acid through the 5-lipoxygenase/ LTC 4 synthase pathway (1, 2). Intracellularly synthesized LTC 4 is exported via multidrug resistance-associated proteins and is rapidly metabolized in the extracellular space by cleavage removal of glutamic acid and then glycine to LTD 4 and LTE 4 , respectively. The type 1 cys-LT receptor (CysLT 1 R) is the high affinity receptor for LTD 4 , whereas the type 2 receptor (CysLT 2 R) can bind both LTC 4 and LTD 4 with one-log less affinity than that of CysLT 1 R for LTD 4 in transfected cells (3, 4). The cys-LTs are mediators of bronchial asthma on the basis of their potent bronchoconstrictive activity via the CysLT 1 R in pharmacologic studies and the clinical effectiveness of CysLT 1 R antagonists (5, 6).LTE 4 , the most abundant cys-LT at sites of inflammation due to its stab...

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confidence: 99%

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Kanaoka

Maekawa

Austen

2013

Journal of Biological Chemistry

159

154

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“…Substantial evidence suggests that CysLTs play an important role in eosinophilic airway inflammation. Intratracheal administration of LTD 4 promotes eosinophil sequestration into the airways (5,6). CysLTR antagonists reduce eosinophilic inflammation of the airways in asthma (7,8).…”

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confidence: 99%

Up-Regulation of Cysteinyl Leukotriene 1 Receptor by IL-13 Enables Human Lung Fibroblasts to Respond to Leukotriene C4 and Produce Eotaxin

Chibana

Ishii

Asakura

et al. 2003

The Journal of Immunology

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Cysteinyl leukotrienes (CysLTs) play an important role in eosinophilic airway inflammation. In addition to their direct chemotactic effects on eosinophils, indirect effects have been reported. Eotaxin is a potent eosinophil-specific chemotactic factor produced mainly by fibroblasts. We investigated whether CysLTs augment eosinophilic inflammation via eotaxin production by fibroblasts. Leukotriene (LT)C4 alone had no effect on eotaxin production by human fetal lung fibroblasts (HFL-1). However, LTC4 stimulated eotaxin production by IL-13-treated fibroblasts, thereby indirectly inducing eosinophil sequestration. Unstimulated fibroblasts did not respond to LTC4, but coincubation or preincubation of fibroblasts with IL-13 altered the response to LTC4. To examine the mechanism(s) involved, the expression of CysLT1R in HFL-1 was investigated by quantitative real-time PCR and flow cytometry. Only low levels of CysLT1R mRNA and no CysLT1R protein were expressed in unstimulated HFL-1. In contrast, stimulation with IL-13 at a concentration of 10 ng/ml for 24 h significantly up-regulated both CysLT1R mRNA and protein expression in HFL-1. The synergistic effect of LTC4 and IL-13 on eotaxin production was abolished by CysLT1R antagonists pranlukast and montelukast. These findings suggest that IL-13 up-regulates CysLT1R expression, which may contribute to the synergistic effect of LTC4 and IL-13 on eotaxin production by lung fibroblasts. In the Th2 cytokine-rich milieu, such as that in bronchial asthma, CysLT1R expression on fibroblasts might be up-regulated, thereby allowing CysLTs to act effectively and increase eosinophilic inflammation.

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“…CysLTs are released by most cells involved in the airways inflammation and particularly by eosinophils (Shaw et al, 1984). Inhalation of LTE4 (Laitinen et al, 1993) or LTD4 (Diamant et al, 1997) induces the recruitment of eosinophils in the airways, possibly in part by inducing P-selectin expression on endothelial cells (Datta et al, 1995). CysLT1 receptors are expressed in human eosinophils (Figueroa et al, 2001), and their activation by CysLTs may lead to eosinophil recruitment to inflammatory sites.…”

Section: Discussionmentioning

confidence: 99%

The effects of low dose leukotriene receptor antagonist therapy on airway remodeling and cysteinyl leukotriene expression in a mouse asthma model

Muz

Deveci²,

Bulut³

et al. 2006

Exp Mol Med

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Airway structural changes that occur in patients with asthma in response to persistent inflammation are termed airway remodeling. The cysteinyl leukotrienes (LTC 4 , D 4 and E 4 ) are known to play important roles in the pathobiology of asthma. To evaluate the effect of low dose montelukast (MK) on the development of airway remodeling using a chronic murine model of allergic airway inflammation with subepithelial fibrosis, BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on days 0 and 14, received intranasal OVA periodically on days 14-75. MK treated mice received montelukast sodium intraperitoneally on days 26-75. The OVA sensitized/challenged mice developed an extensive eosinophil cell inflammatory response, goblet cell hyperplasia, mucus occlusion, and smooth muscle hypertrophy of the airways. In addition, in OVA sensitized/challenged mice, dense collagen deposition/fibrosis was seen throughout the lung interstitium surrounding the airways, blood vessels, and alveolar septae. The cysteinyl leukotriene 1 (CysLT1) receptor antagonist, MK significantly reduced the airway eosinophil infiltration, goblet cell hyperplasia, mucus occlusion, and lung fibrosis except airway smooth muscle hypertrophy in the OVA sensitized/challenged mice. The OVA sensitized/challenged mice had significantly increased epithelial desquamation compared with control mice. MK markedly reduced epithelial desquamation of airways in OVA/MK treated animals compared with OVA sensitized/challenged mice. MK treatment did not affect the levels of CysLT in lung tissue. Our results show that the important role of cysteinyl leukotrienes in the pathogenesis of asthma. Lower dose of CysLT1 receptor antagonism has a significant anti-inflammatory effect on allergen-induced lung inflammation and fibrosis but not airway smooth muscle hypertrophy in an animal model of asthma.

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Leukotriene E4 and granulocytic infiltration into asthmatic airways

Cited by 486 publications

References 7 publications

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Identification of GPR99 Protein as a Potential Third Cysteinyl Leukotriene Receptor with a Preference for Leukotriene E4 Ligand

Up-Regulation of Cysteinyl Leukotriene 1 Receptor by IL-13 Enables Human Lung Fibroblasts to Respond to Leukotriene C4 and Produce Eotaxin

The effects of low dose leukotriene receptor antagonist therapy on airway remodeling and cysteinyl leukotriene expression in a mouse asthma model

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