CysLT1 receptor upregulation by TGF-β and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4

Espinosa, Karina; Bossé, Ynuk; Staňková, Jana; Rola‐Pleszczynski, Marek

doi:10.1067/mai.2003.1451

Cited by 163 publications

(123 citation statements)

References 38 publications

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“…These findings are in accord with and expand on those of Perng et al (53), who demonstrated that LTC 4 has the ability to stimulate epithelial cell TGF-␤ 1 . It is important to point out that TGF-␤ 1 also up-regulates the expression of LT receptors such as cys-LT1 (29) and primes a variety of cells for enhanced LT production (54). When viewed in combination, one can envision a positive feedback loop with IL-13 activating 5-LO and stimulating LT production, which, in turn, contributes to the production and activation of TGF-␤ 1 .…”

Section: Discussionmentioning

confidence: 99%

“…Exaggerated levels of the cys-LTs have been documented in asthma, where they contribute to asthmatic smooth muscle contraction, bronchospasm, microvascular permeability, mucous hypersecretion, airway remodeling, and eosinophilic inflammation (24 -28). IL-13 has also been shown to regulate the production of cys-LTs and cys-LT receptor expression (29,30), and cys-LTs have been shown to play a role in the pathogenesis of the acute effects of IL-13 and Th2 cytokines (31,32). In accord with the importance of these tissue responses, agents that block 5-LO or cys-LTs have been given Food and Drug Administration approval as asthma therapeutics (33,34).…”

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confidence: 98%

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Role of 5-Lipoxygenase in IL-13-Induced Pulmonary Inflammation and Remodeling

Shim

Zhu

Zheng

et al. 2006

The Journal of Immunology

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Exaggerated levels of IL-13 and leukotriene (LT) pathway activation frequently coexist at sites of Th2 inflammation and in tissue fibrotic responses. However, the relationship(s) between the IL-13 and LTs in these responses have not been defined. We hypothesized that the 5-lipoxygenase (5-LO) pathway of LT metabolism plays an important role in the pathogenesis of IL-13-induced chronic inflammation and remodeling. To test this hypothesis, we evaluated the effects of IL-13 on components of the 5-LO metabolic and activation pathways. We also compared the effects of transgenic IL-13 in C57BL/6 mice with wild-type and null 5-LO genetic loci. These studies demonstrate that IL-13 increases the levels of mRNA encoding cytosolic phospholipase A2, LTA4 hydrolase, and 5-LO-activating protein without altering the expression of 5-LO, LTC4 synthase, LTB4 receptors 1 and 2, and cysteinyl-LT receptors 1 and 2. They also demonstrate that this activation is associated with the enhanced accumulation of LTB4 but not of cysteinyl-LTs. Furthermore, they demonstrate that this stimulation plays a critical role in the pathogenesis of IL-13-induced inflammation, tissue fibrosis, and respiratory failure-induced death while inhibiting alveolar remodeling. Lastly, mechanistic insights are provided by demonstrating that IL-13-induced 5-LO activation is required for optimal stimulation and activation of TGF-β1 and the inhibition of matrix metalloproteinase-12. When viewed in combination, these studies demonstrate that 5-LO plays an important role in IL-13-induced inflammation and remodeling.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

Role of 5-Lipoxygenase in IL-13-Induced Pulmonary Inflammation and Remodeling

Shim

Zhu

Zheng

et al. 2006

The Journal of Immunology

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“…The observation that HLMC not only degranulate but also metabolise arachidonic acid and synthesise cytokines in response to IgE suggests that several diverse tissue effects will ensue. For example, histamine is a bronchoconstrictor, tryptase is an ASM mitogen [24], cysteinyl leukotrienes are potent bronchoconstrictors and potentiate ASM proliferation following exposure to IL-13 [25], while IL-8 is also a potent smooth muscle mitogen [26]. Furthermore, since concentrations of SCF are elevated in asthmatic airways [17], and SCF is a product of ASM [27], it is easy to envisage a positive feedback loop whereby monomeric IgE together with ASM-derived SCF activates mast cells, which in turn activate ASM.…”

Section: Discussionmentioning

confidence: 99%

Activation of human lung mast cells by monomeric immunoglobulin E

Cruse¹

2005

Eur Respir J

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The mechanism of chronic mast cell activation in asthma is unclear. Monomeric immunoglobulin (Ig)E in the absence of allergen induces mediator release from rodent mast cells, indicating a possible role for IgE in the continued activation of mast cells within the asthmatic bronchial mucosa. In this study it was investigated whether monomeric IgE induces Ca 2+ influx and mediator release from human lung mast cells (HLMC). Purified HLMC were cultured for 4 weeks and then exposed to monomeric human myeloma IgE. Ratiometric Ca 2+ imaging was performed on single fura-2-loaded cells. Histamine release was measured by radioenzymatic assay; leukotriene C 4 (LTC 4 ) and interleukin (IL)-8 were measured by ELISA. At concentrations experienced in vivo, monomeric IgE induced dose-dependent histamine release, LTC 4 production and IL-8 synthesis. This was associated with a rise in cytosolic free Ca 2+ . Enhanced histamine release was still evident 1 week after initial exposure to IgE suggesting that continued exposure maintains enhanced secretion.Monomeric immunoglobulin E alone activates cultured human lung mast cells initiating Ca 2+ influx, degranulation, arachidonic acid metabolism and cytokine synthesis. These findings support the hypothesis that immunoglobulin E loading of mast cells within the asthmatic airway contributes to the disordered airway physiology of this disease.

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“…However, addition of the leukotrienes LTC 4 and LTB 4 to ASMC cultures did not elicit ASMC proliferation per se. In accordance, it was recently shown that cysteinyl leukotrienes alone did not induce proliferation, but acted in synergy with other factors [36][37][38]. Some studies indicate for a link between eicosanoids and ROS production [14,[22][23][24].…”

Section: Discussionmentioning

confidence: 56%

Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species

et al. 2008

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Continuous recruitment and inappropriate activity of platelets in the airways may contribute to airway remodeling, a characteristic feature of inflammatory airway diseases that includes increased proliferation of the smooth muscle. The aim of the present investigation was to examine the effect of platelets on proliferation of airway smooth muscle cells (ASMC) in culture and to determine the possible role of 5-lipoxygenase (5-LOX) and reactive oxygen species (ROS) in this context. ASMC obtained from guinea pigs were cultured and co-incubated with washed platelets for 24 hours. Thereafter, the proliferation was measured with the MTS-assay, the results were also verified by using thymidine incorporation, DNA measurements and manual counting. The interaction between platelets and ASMC was visualised with fluorescence microscopy. We found that platelets bind to the ASMC and the presence of platelets caused a significant dose-dependent increase in ASMC proliferation. Co-incubation of ASMC with platelets also increased ROS-production, detected by the fluorescent probe DCFDA. Furthermore, the platelet-induced proliferation was reduced in the presence of the NADPH-oxidase inhibitors DPI and apocynin. A possible role of 5-LOX in platelet-induced proliferation and ROS-generation was evaluated by using the 5-LOX inhibitor AA-861 and the PLA2-inhibitor ATK. The results showed that inhibition of these enzymes significantly reduced the platelet-induced proliferation. Moreover, Western blot analysis revealed that the ASMC but not the platelets express 5-LOX. In addition, our experiments revealed that the presence of AA-861 and ATK significantly inhibited the ROS-production generated upon coincubation of platelets and ASMC. In conclusion, we show that platelets have a marked capacity to induce ASMC proliferation. Furthermore, our study indicates that the interaction between platelets and ASMC leads to activation of 5-LOX in the ASMC followed by an increased ROS-production, events resulting in enhanced ASMC proliferation. The new findings are of importance in understanding possible mechanisms contributing to airway remodeling.Original publication: Ann-Charlotte B. Svensson Holm, Torbjörn Bengtsson, Magnus Grenegård and Eva G. Lindström, Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species, 2008, Platelets, (19), 7, 528-536.http://dx.doi.org/10.1080/09537100802320300. Copyright © Taylor & Francis Group, an informa busines

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CysLT1 receptor upregulation by TGF-β and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4

Cited by 163 publications

References 38 publications

Role of 5-Lipoxygenase in IL-13-Induced Pulmonary Inflammation and Remodeling

Role of 5-Lipoxygenase in IL-13-Induced Pulmonary Inflammation and Remodeling

Activation of human lung mast cells by monomeric immunoglobulin E

Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species

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