Sildenafil Prevents Marfan-Associated Emphysema and Early Pulmonary Artery Dilation in Mice

White, Zoe; Milad, Nadia; Tehrani, Arash Y.; Lamothe, Jennifer; Hogg, James C.; Esfandiarei, Mitra; Seidman, Michael A.; Booth, Steven; Hackett, Tillie-Louise; Morissette, Mathieu C.; Bernatchez, Pascal

doi:10.1016/j.ajpath.2019.05.003

Cited by 12 publications

(12 citation statements)

References 53 publications

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“…We did not study the effects of anti-IL11RA therapy on pulmonary artery dilatation in the Fbn1 C1041G/+ mouse which has been previously reported to be elevated. 59 It should be noted that neither the global knockout of IL11/RA nor the treatment with anti-IL11/RA therapies are expected to alter blood pressure in mice. 23 , 60 Inflammatory cell infiltrates in the mMFS lung were assessed by CD68 staining for macrophages and does not detect other immune cell types such as neutrophils which are known to contribute to emphysema.…”

Section: Discussionmentioning

confidence: 99%

IL11 (Interleukin-11) Causes Emphysematous Lung Disease in a Mouse Model of Marfan Syndrome

Xie

et al. 2023

ATVB

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BACKGROUND: Marfan Syndrome (MFS) is an inherited connective tissue disorder caused by mutations in the FBN1 (fibrillin-1) gene. Lung abnormalities are common in MFS, but their pathogenesis is poorly understood. IL11 (interleukin-11) causes aortic disease in a mouse model of MFS and was studied here in the lung. METHODS: We examined histological and molecular phenotypes in the lungs of Fbn1 C1041G/+ mice (mouse model of Marfan Syndrome [mMFS]), an established mouse model of MFS. To identify IL11-expressing cells, we used immunohistochemistry on lungs of 4- and 16-week-old Fbn1 C1041G/+ : Il11 EGFP/+ reporter mice. We studied the effects of IL11 inhibition by RT-qPCR, immunoblots and histopathology in lungs from genetic or pharmacologic models: (1) 16-week-old IL11 receptor (IL11RA) knockout mMFS mice ( Fbn1 C1041G/+ : Il11ra1 − /− mice) and (2) in mMFS mice administered IgG control or interleukin-11 receptor antibodies twice weekly from 4 to 24 weeks of age. RESULTS: mMFS lungs showed progressive loss and enlargement of distal airspaces associated with increased proinflammatory and profibrotic gene expression as well as matrix metalloproteinases 2, 9, and 12. IL11 was increased in mMFS lungs and localized to smooth muscle and endothelial cells in young mMFS mice in the Fbn1 C1041G/+ : Il11 EGFP/+ reporter strain and in fibroblasts, in older mice. In mMFS mice, genetic ( Fbn1 C1041G/+ : Il11ra1 − /− ) or pharmacologic (anti-interleukin-11 receptor) inhibition of IL11 signaling reduced lung emphysema, fibrosis, and inflammation. This protective effect was associated with reduced pathogenic ERK1/2 signaling and lower metalloproteinase 2, 9, and 12 expression. CONCLUSIONS: IL11 causes lung disease in mMFS. This reveals a shared IL11-driven disease mechanism in lung and aorta in MFS and suggests inhibition of IL11 signaling as a holistic approach for treating multiorgan morbidity in MFS.

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Section: Discussionmentioning

confidence: 99%

IL11 (Interleukin-11) Causes Emphysematous Lung Disease in a Mouse Model of Marfan Syndrome

Xie

et al. 2023

ATVB

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“…The Mean ± SD were utilized from our and other previously published data to reach a 20% reduction in aortic root dilation (as evident by using ultrasound imaging) in MFS mice in response to intervention (N=10/group/sex). 12,13,62…”

Section: Methodsmentioning

confidence: 99%

In VivoPhenotypic Vascular Dysfunction Extends Beyond the Aorta in a Mouse Model for Fibrillin-1 (FBN1) Mutation

Curry,

Barrameda,

Currier Thomas

et al. 2023

Preprint

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In individuals with Marfan Syndrome (MFS), fibrillin-1 gene (FBN1) mutations can lead to vascular wall weakening and dysfunction. The experimental mouse model of MFS (FBN1C1041G/+) has been advantageous in investigating MFS-associated life-threatening aortic aneurysms. Although the MFS mouse model presents an accelerated-aging phenotype in elastic organs (e.g., lung, skin), the impact ofFBN1mutations on other central and peripheral arteries function and structure with the consideration of the impact of sex remains underexplored. In this study, we investigate ifFBN1mutation contributes to sex-dependent alterations in central and cerebral vascular function similar to phenotypic changes associated with normal aging in healthy control mice.In vivoultrasound imaging of central and cerebral vasculature was performed in 6-month-old male and female MFS and C57BL/6 mice and sex-matched 12-month-old (middle-aged) healthy control mice. Our findings confirm aortic enlargement (aneurysm) and wall stiffness in MFS mice, but with exacerbation in male diameters. Coronary artery blood flow velocity (BFV) in diastole was not different but left pulmonary artery BFV was decreased in MFS and 12-month-old control mice regardless of sex. At 6 months of age, MFS male mice show decreased posterior cerebral artery BFV as compared to age-matched control males, with no difference observed between female cohorts. Reduced mitral valve early-filling velocities were indicated in MFS mice regardless of sex. Male MFS mice also demonstrated left ventricular hypertrophy. Overall, these results underscore the significance of biological sex in vascular function and structure in MFS mice, while highlighting a trend of pre-mature vascular aging phenotype in MFS mice that is comparable to phenotypes observed in older healthy controls.

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“…Lung capacity: Lung function was assessed using the FlexiVent® (SCIREQ; Montréal, Canada) as previously described 56 . Briefly, mice were anaesthetised with 100 mg/kg ketamine and 10 mg/kg xylazine, tracheotomized with an 18-gauge blunt needle and mechanically ventilated at a respiratory rate of 150 breaths/min and a tidal volume of 10 mL/kg, with a pressure limit of 30 cmH2O.…”

Section: Cytofmentioning

confidence: 99%

Mesenchymal Progenitors set the homeostatic inflammatory milieu via the TAK1-NFkB axis

Théret

Messing

White

et al. 2022

Preprint

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The ability of mesenchymal stromal cells to modulate inflammation is at the basis of the ongoing interest in their therapeutic potential. Yet, reliable success in clinical trials is limited, possibly due to a limited understanding of their impact on the inflammatory milieu in physiological conditions. Here we show that, at steady state, mesenchymal progenitors regulate the balance between type 1 and type 2 inflammatory milieus by acting on innate immune cells through the TAK1-NFkB pathway. Suppressing the constitutive activity of this pathway in MPs leads to skewing of the immune system toward systemic Type 2 inflammation (Th2). These changes have significant effects on diseases with an important inflammatory component, leading to a worsening of disease in a preclinical model of Th2-dependent Asthma, and a reduction of symptoms associated with Th1/Th17-dependent experimental autoimmune encephalitis.

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Sildenafil Prevents Marfan-Associated Emphysema and Early Pulmonary Artery Dilation in Mice

Cited by 12 publications

References 53 publications

IL11 (Interleukin-11) Causes Emphysematous Lung Disease in a Mouse Model of Marfan Syndrome

IL11 (Interleukin-11) Causes Emphysematous Lung Disease in a Mouse Model of Marfan Syndrome

In VivoPhenotypic Vascular Dysfunction Extends Beyond the Aorta in a Mouse Model for Fibrillin-1 (FBN1) Mutation

Mesenchymal Progenitors set the homeostatic inflammatory milieu via the TAK1-NFkB axis

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