Cysteinyl Leukotrienes Are Autocrine and Paracrine Regulators of Fibrocyte Function

Vannella, Kevin M.; McMillan, Tracy R.; Charbeneau, Ryan P.; Wilke, Carol A.; Thomas, Peedikayil E.; Toews, Galen B.; Peters‐Golden, Marc; Moore, Bethany B.

doi:10.4049/jimmunol.179.11.7883

Cited by 65 publications

(63 citation statements)

References 40 publications

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“…This is the first description of the ability of AECs to produce LTs. CysLT levels are elevated in patients with IPF (27), and LTdeficient mice are protected from experimental fibrosis (28,29). It is possible that the increased cysLT production in AECs induces the secretion of TGF-b1.…”

Section: Discussionmentioning

confidence: 99%

“…The production of cysLTs by latently infected AECs is likely to promote fibrosis via effects on mesenchymal cells. We have previously reported that cysLTs can cause fibrocytes to proliferate (29). Additionally, cysLTs are known to induce fibroblast proliferation (44) and collagen secretion (45).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, we have previously demonstrated that cysLTs have potent proliferative effects on fibrocytes (29). Thus, we investigated whether latent infection of AECs augmented the production of cysLTs.…”

Section: Latent Ghv-68 Infection Induces Cyslt Production In Aecsmentioning

confidence: 94%

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Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

Vannella¹,

Luckhardt²,

Wilke³

et al. 2010

Am J Respir Crit Care Med

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Rationale: No effective treatment exists for idiopathic pulmonary fibrosis, and its pathogenesis remains unclear. Accumulating evidence implicates herpesviruses as cofactors (either initiating or exacerbating agents) of fibrotic lung disease, but a role for latent herpesvirus infection has not been studied. Objectives: To develop a murine model to determine whether latent herpesvirus infection can augment fibrotic responses and to gain insight into potential mechanisms of enhanced fibrogenesis. Methods: Mice were infected with murine gherpesvirus 14 to 70 days before a fibrotic challenge with fluorescein isothiocyanate or bleomycin so that the virus was latent at the time of fibrotic challenge. Measurements were made after viral infection alone or after the establishment of fibrosis. Measurements and Main Results: gHerpesvirus is latent by 14 days post infection, and infection 14 to 70 days before fibrotic challenge augmented fibrosis. Fibrotic augmentation was not dependent on reactivation of the latent virus to a lytic state. Total cell numbers and fibrocyte numbers were increased in the lungs of latently infected mice administered fibrotic challenge compared with mock-infected mice that received fibrotic challenge. Latent infection up-regulates expression of proinflammatory chemokines, transforming growth factor-b1, and cysteinyl leukotrienes in alveolar epithelial cells. Conclusions: Latent gherpesvirus infection augments subsequent fibrotic responses in mice. Enhanced fibrosis is associated with the induction of profibrotic factors and the recruitment of fibrocytes. Our data complement existing human and animal data supporting the hypothesis that gherpesviruses can serve as initiating cofactors in the pathogenesis of pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

Vannella¹,

Luckhardt²,

Wilke³

et al. 2010

Am J Respir Crit Care Med

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“…They promote the proliferation of human bone marrowderived fibroblasts, which participate in tissue remodeling and repair 8) . Also human bronchial fibroblasts can produce both LT B4 and cysteinyl LTs 9) .…”

Section: Introductionmentioning

confidence: 99%

Leukotrienes B4, C4, D4 and E4 in the Exhaled Breath Condensate (EBC), Blood and Urine in Patients with Pneumoconiosis

Pelclová¹,

Fenclová²,

Vlčková³

et al. 2012

Ind Health

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Leukotrienes (LTs) are involved in the pathogenesis of lung fibrosis and were increased in exhaled breath condensate (EBC) of the patients with pneumoconiosis. However the possible influence of extra-pulmonary disorders on the EBC markers is not known. Therefore in parallel with EBC, LTs' levels in the plasma and urine were measured in patients with pneumoconiosis (45 × asbestos exposure, 37 × silica exposure) and in 27 controls. Individual LTs B4, C4, D4 and E4 were measured by liquid chromatography − electrospray ionization − tandem mass spectrometry (LC-ESI-MS/MS). In EBC, LT D4 and LT E4 were increased in both groups of patients (p<0.001 and p<0.05), comparing with the controls. Both LT B4 and cysteinyl LTs were elevated in asbestosexposed subjects (p<0.05). Asbestosis with more severe radiological signs (s1/s2-t3/u2) and lung functions impairment has shown higher cysteinyl LTs and LT C4 in the EBC (p<0.05) than mild asbestosis (s1/s0-s1/s1). In addition, in the subjects with asbestosis, cysteinyl LTs in EBC correlated with TLC (−0.313, p<0.05) and TLCO/Hb (−0.307, p<0.05), and LT C4 with TLC (−0.358, p<0.05). In pneumoconioses, EBC appears the most useful from the 3 fluids studied.

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“…Medina et al demonstrated that LTD 4 and IL-1β could induce the secretion of MMP-1 in airway smooth muscle cells resulting in the stimulation of cell proliferation [30]. More recently, it has been suggested that LTD 4 has the potential to augment fibroblast chemotaxis, and to contribute to the regulation of the wound healing and remodeling in fibrotic processes of the lung [31,32]. LTD 4 may also increase collagen production in activated myofibroblasts by upregulating CysLT1 receptor induced by TGF-β 1 [33].…”

Section: Discussionmentioning

confidence: 99%

LTD4 and TGF-β1 Induce the Expression of Metalloproteinase-1 in Chronic Rhinosinusitis via a Cysteinyl Leukotriene Receptor 1-Related Mechanism

et al. 2016

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Background: Cysteinyl leukotrienes (CysLTs) play a crucial role in the pathogenesis of airway remodeling. The use of CysLTs receptor antagonists has been included in the management of asthma and rhinitis. However, despite the action of these compounds on leukotriene production has been well documented, their role in airway remodeling remains unclear. Objective: We aimed to investigate the capability of the leukotriene receptor antagonist Montelukast to inhibit MMPs release after CysLTs stimulation in nasal tissue fibroblasts. Methods: Fibroblasts were isolated from sinunasal tissue collected from five patients suffering of chronic rhinosinusitis without nasal polyposis. Cells were cultured and stimulated first with LTC4 and LTD4 (10−10, 10−8, 10−6 M) using as pre-stimulus 10 ng/mL of: IL-4, IL-13, or TGF-beta1 and in presence or absence of Montelukast (10−10, 10−8, 10−6 M). To evaluate the regulation of MMP-1 and TIMP-1 we used enzyme immunoassays and to evaluate CysLT1 receptor we used real time PCR. Results: LTD4 but not LTC4 induced production of mRNA for CysLT1 receptor in a dose dependent manner and with an additive effect when the cells where primed with TGF-β1. TNF-α, IL-4, and IL-13 did not influence the expression of the receptor. Levels of MMP-1 but not of TIMP-1 were statistically enhanced in cells primed with TGF-β1 and stimulated with LTD4. Montelukast significantly decreased Cys-LT1 receptor and MMP-1 concentrations in a dose-dependent way in cells stimulated with LTD4 and TGF-β1 separately and when they were applied together. Conclusion: The leukotriene pathway may play an important role in extra-cellular matrix formation in an inflamed environment, such as chronic sinusitis and, consequently, leukotriene receptor antagonists such as Montelukast may be of great benefit in management of this disease.

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Cysteinyl Leukotrienes Are Autocrine and Paracrine Regulators of Fibrocyte Function

Cited by 65 publications

References 40 publications

Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

Latent Herpesvirus Infection Augments Experimental Pulmonary Fibrosis

Leukotrienes B4, C4, D4 and E4 in the Exhaled Breath Condensate (EBC), Blood and Urine in Patients with Pneumoconiosis

LTD4 and TGF-β1 Induce the Expression of Metalloproteinase-1 in Chronic Rhinosinusitis via a Cysteinyl Leukotriene Receptor 1-Related Mechanism

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