Simultaneous PET and molecular MR imaging of cardiopulmonary fibrosis in a mouse model of left ventricular dysfunction DOI Creative Commons
Brianna F. Moon, Iris Y. Zhou, Yingying Ning

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 17, 2023

Abstract Background Aging-associated left ventricular (LV) dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right failure. At the time of diagnosis, cardiac function has declined, fibrosis often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol detect both fibrotic disease activity in an LV model. Methods was induced by transverse aortic constriction (TAC) 6-month-old senescence-accelerated prone (SAMP8) mice, subset mice received sham surgery. Three weeks post-surgery, underwent simultaneous PET-MR at 4.7 T. Collagen–targeted PET fibrogenesis MR probes were intravenously administered. signal computed as myocardium- or lung-to-muscle ratio (MMR, LMR). Percent increase (%SI) ΔLMR from pre-/post-injection images. Tissue specimens analyzed for hydroxyproline (Hyp) allysine content. Ventricular structure measured echocardiography hemodynamic pressure-volume (PV) loop analysis. Results Allysine heart (22±5 (TAC), 13±5 (sham) nmol/g, P=0.02 ) lungs (7.5±4 5.8±2 nmol/lung, P=0.17 TAC corresponded myocardial MRI %SI (29±15 6.1±4 (sham), P<0.0001 (0.3±0.1 0.08±0.1 ). Hyp (555±90 400±80 µg/g, (189±63 143±31 µg/lung, P<0.01 elevated which (MMR: 1.8±0.1 1.6±0.2 ; LMR: 1.5±0.1 1.2±0.1 P<0.001 PV demonstrated adverse function, increased systolic pressure mice. Conclusions Administration collagen-targeted allysine-targeted led PET-MRI signals myocardium The study demonstrates potential through dual protocol.

Language: Английский

The vascular perspective on acute and chronic lung disease DOI Creative Commons
Izabela Borek, Anna Birnhuber,

Norbert F. Voelkel

et al.

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(16)

Published: Aug. 14, 2023

The pulmonary vasculature has been frequently overlooked in acute and chronic lung diseases, such as respiratory distress syndrome (ARDS), fibrosis (PF), obstructive disease (COPD). primary emphasis the management of these parenchymal disorders largely revolved around injury aberrant repair epithelial cells. However, there is increasing evidence that vascular endothelium plays an active role development diseases. endothelial cell network capillary bed arterial venous vessels provides a metabolically highly barrier controls migration immune cells, regulates tone permeability, participates remodeling processes. Phenotypically functionally altered remodeled vessels, can be found although to different degrees, likely because disease-specific mechanisms. Since associated with hypertension, which worsens patient outcomes survival, it crucial understand underlying alterations. In this Review, we describe current knowledge regarding progression ARDS, PF, COPD; also outline future research directions hope facilitating mechanism-based therapies.

Language: Английский

Citations

36
Understanding interleukin 11 as a disease gene and therapeutic target DOI Creative Commons
Stuart A. Cook

Biochemical Journal, Journal Year: 2023, Volume and Issue: 480(23), P. 1987 - 2008

Published: Dec. 6, 2023

Interleukin 11 (IL11) is an elusive member of the IL6 family cytokines. While initially thought to be a haematopoietic and cytoprotective factor, more recent data show instead that IL11 redundant for haematopoiesis toxic. In this review, reasons led original misunderstandings biology, which are now understandable, explained with particular attention on use recombinant human in mice humans. Following tissue injury, as part evolutionary ancient homeostatic response, secreted from damaged mammalian cells signal via JAK/STAT3, ERK/P90RSK, LKB1/mTOR GSK3β/SNAI1 autocrine paracrine. This activates program mesenchymal transition epithelial, stromal, endothelial cause inflammation, fibrosis, stalled endogenous repair, leading organ failure. The role signalling cell- organ-specific pathobiology described, large unknowns about biology discussed promise targeting therapeutic approach reviewed.

Language: Английский

Citations

26
Cardiomyocyte-Restricted Expression of IL11 Causes Cardiac Fibrosis, Inflammation, and Dysfunction DOI Open Access
Mark Sweeney,

Katie O’Fee,

Chelsie Villanueva-Hayes

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12989 - 12989

Published: Aug. 20, 2023

Cardiac fibrosis is a common pathological process in heart disease, representing therapeutic target. Transforming growth factor β (TGFβ) the canonical driver of cardiac and was recently shown to be dependent on interleukin 11 (IL11) for its profibrotic effects fibroblasts. In opposite direction, recombinant human IL11 has been reported as anti-fibrotic anti-inflammatory mouse heart. this study, we determined expression cardiomyocytes pathobiology function. We used Cre-loxP system generate tamoxifen-inducible with cardiomyocyte-restricted murine

Language: Английский

Citations

15
Mechanisms and therapeutic research progress in intestinal fibrosis DOI Creative Commons

Yanjiang Liu,

Tao Zhang, Kejian Pan

et al.

Frontiers in Medicine, Journal Year: 2024, Volume and Issue: 11

Published: June 14, 2024

Intestinal fibrosis is a common complication of chronic intestinal diseases with the characteristics fibroblast proliferation and extracellular matrix deposition after inflammation, leading to lumen narrowing, structural functional damage intestines, life inconvenience for patients. However, anti-inflammatory drugs are currently generally not effective in overcoming making surgery main treatment method. The development slow process its onset may be result combined action inflammatory cells, local cytokines, stromal cells. aim this study elucidate pathogenesis [e.g., (ECM), cytokines chemokines, epithelial-mesenchymal transition (EMT), differentiation myofibroblast microbiota] underlying explore therapeutic advances (such as regulating ECM, EMT, targeting TGF- β ) based on order gain new insights into prevention fibrosis.

Language: Английский

Citations

6
Interleukin-11 and its eminent role in tissue fibrosis: a possible therapeutic target DOI Open Access
Steven O’Reilly

Clinical & Experimental Immunology, Journal Year: 2023, Volume and Issue: 214(2), P. 154 - 161

Published: Sept. 19, 2023

Interleukin-11 is a cytokine from the IL-6 family of cytokines that includes and oncostatin-M. Initially described for its role in platelet generation, it now appreciated this has multiple functions. Recently been found IL-11 critical fibrosis different organ systems systemically as autoimmune disease systemic sclerosis. Animal models have determined animals with receptor deletions retarded wild-type at fibrosis. Recent evidence suggests may be master regulator regardless end target organ. With development neutralizing antibodies targeting pre-clinical could possible therapeutic, which no specific therapies exist. This review appraises tissue fibrosis, signalling properties, therapeutic targeting. The ends an appraisal indications modulation targeted.

Language: Английский

Citations

13
Mechanisms of Bleomycin-induced Lung Fibrosis: A Review of Therapeutic Targets and Approaches DOI
Shaimaa M. Mohammed,

Haider Falih Shamikh Al-Saedi,

Amjed Qasim Mohammed

et al.

Cell Biochemistry and Biophysics, Journal Year: 2024, Volume and Issue: 82(3), P. 1845 - 1870

Published: July 2, 2024

Language: Английский

Citations

4
Time-course Transcriptomics Reveals the Impact of Treponema pallidum on Microvascular Endothelial Cell Function and Phenotype DOI
Sean Waugh, Mara C. Goodyear,

Alloysius Gomez

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: May 6, 2025

Summary Syphilis, caused by Treponema pallidum subsp. pallidum, is an urgent global public health threat. Syphilis vaccine development has been impeded limited understanding of the molecular mechanisms that enable T. to establish and maintain infection. The vascular endothelium critical for attachment, dissemination, host immune response initiation; however, details -endothelial interactions are incompletely understood. To enhance understanding, we performed time-course transcriptomic profiling on -exposed brain microvascular endothelial cells. These analyses showed exposure altered pathways related extracellular matrix, growth factors, integrins, Rho GTPases. induced transcriptional was consistent with mesenchymal transition, a process involved in fetal dysfunction. This study provides comprehensive responses cells identified might cause syphilis disease symptoms, information could aid design. Highlights □ Exposure Pallidum significantly alters cell transcriptome Signaling matrix organization, GTPases were overrepresented genes differentially expressed induces factors central may explain devastating effects congenital infection expression Snail, main transcription factor associated transition

Language: Английский

Citations

0
IL11-mediated stromal cell activation may not be the master regulator of pro-fibrotic signaling downstream of TGFβ DOI Creative Commons
Yunhao Tan, Kenta Mosallanejad,

Qingxiu Zhang

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 22, 2024

Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified central mechanism for promoting downstream of TGFβ. IL11 signaling recently reported to promote fibroblast-to-myofibroblast transition, thus leading various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression IL11Rα in fibrotic diseases by OMICs approaches situ hybridization. However, the vital role driver was not recapitulated. While induction secretion observed TGFβ human lung fibroblasts epithelial cells, cellular responses induced quantitatively qualitatively inferior that at transcriptional translational levels. blocking antibodies inhibited IL11Rα-proximal STAT3 but failed block TGFβ-induced profibrotic signals. In summary, our results challenge concept blockade strategy providing transformative treatment fibrosis.

Language: Английский

Citations

3
IL11 (Interleukin-11) Causes Emphysematous Lung Disease in a Mouse Model of Marfan Syndrome DOI Creative Commons
Benjamin Ng, Chen Xie, Liping Su

et al.

Arteriosclerosis Thrombosis and Vascular Biology, Journal Year: 2023, Volume and Issue: 43(5), P. 739 - 754

Published: March 16, 2023

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

Language: Английский

Citations

7
Advances in the research of sulfur dioxide and pulmonary hypertension DOI Creative Commons
Xin Liu, He Zhou, Hongsheng Zhang

et al.

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 12, 2023

Pulmonary hypertension (PH) is a fatal disease caused by progressive pulmonary vascular remodeling (PVR). Currently, the mechanisms underlying occurrence and progression of PVR remain unclear, effective therapeutic approaches to reverse PH are lacking. Since beginning 21st century, endogenous sulfur dioxide (SO 2 )/aspartate transaminase system has emerged as novel research focus in fields PVR. As gaseous signaling molecule, SO metabolism tightly regulated vasculature associated with development it involved regulation pathological physiological activities, such cellular inflammation, proliferation collagen metabolism, exert protective effect against PH. In this review, we present an overview studies conducted date that have provided theoretical basis for -related drug inhibit or effectively treat PH-related diseases.

Language: Английский

Citations

7