Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities DOI
Ingo Hilgendorf, Stefan Frantz, Nikolaos G. Frangogiannis

et al.

Circulation Research, Journal Year: 2024, Volume and Issue: 134(12), P. 1718 - 1751

Published: June 6, 2024

The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory fibrogenic cascades that ultimately result in formation a scar. After infarction, massive cardiomyocyte death releases broad range damage-associated molecular patterns initiate both myocardial systemic responses. TLRs (toll-like receptors) NLRs (NOD-like recognize (DAMPs) transduce downstream proinflammatory signals, leading to upregulation cytokines (such as interleukin-1, TNF-α [tumor necrosis factor-α], interleukin-6) chemokines CCL2 [CC chemokine ligand 2]) recruitment neutrophils, monocytes, lymphocytes. Expansion diversification cardiac macrophages infarcted play major role clearance infarct from dead cells subsequent stimulation reparative pathways. Efferocytosis triggers induction release anti-inflammatory mediators restrain reaction set stage for fibroblasts vascular cells. Growth factor–mediated pathways, neurohumoral cascades, matricellular proteins deposited provisional matrix stimulate fibroblast proliferation myofibroblast conversion. Deposition well-organized collagen-based extracellular network protects catastrophic rupture attenuates ventricular dilation. Scar maturation requires signals inhibit activity prevent excessive fibrosis. Moreover, mature scar, neovessels acquire mural cell coat contributes stabilization microvascular network. Excessive, prolonged, or dysregulated accentuate adverse remodeling dysfunction. leukocytes can contribute arrhythmogenesis. Inflammatory pathways may be promising therapeutic targets attenuate failure progression arrhythmia generation patients surviving infarction.

Language: Английский

Cardiac fibrosis DOI Open Access
Nikolaos G. Frangogiannis

Cardiovascular Research, Journal Year: 2020, Volume and Issue: 117(6), P. 1450 - 1488

Published: Oct. 26, 2020

Abstract Myocardial fibrosis, the expansion of cardiac interstitium through deposition extracellular matrix proteins, is a common pathophysiologic companion many different myocardial conditions. Fibrosis may reflect activation reparative or maladaptive processes. Activated fibroblasts and myofibroblasts are central cellular effectors in serving as main source proteins. Immune cells, vascular cells cardiomyocytes also acquire fibrogenic phenotype under conditions stress, activating fibroblast populations. Fibrogenic growth factors (such transforming factor-β platelet-derived factors), cytokines [including tumour necrosis factor-α, interleukin (IL)-1, IL-6, IL-10, IL-4], neurohumoral pathways trigger signalling cascades binding to surface receptors, downstream cascades. In addition, matricellular macromolecules deposited remodelling myocardium regulate assembly, while modulating signal transduction protease factor activity. Cardiac can sense mechanical stress mechanosensitive ion channels integrins, intracellular that contribute fibrosis response pressure overload. Although subpopulations fibroblast-like exert important protective actions both interstitial/perivascular ultimately fibrotic changes perturb systolic diastolic function, play an role pathogenesis arrhythmias. This review article discusses molecular mechanisms involved various diseases, including infarction, heart failure with reduced preserved ejection fraction, genetic cardiomyopathies, diabetic disease. Development fibrosis-targeting therapies for patients diseases will require not only understanding functional pluralism dissection basis remodelling, but appreciation heterogeneity fibrosis-associated

Language: Английский

Citations

735
Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis DOI
B.J. Moss, Stefan W. Ryter, Iván O. Rosas

et al.

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2021, Volume and Issue: 17(1), P. 515 - 546

Published: Nov. 23, 2021

The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves a complex interplay cell types and signaling pathways. Recurrent alveolar epithelial (AEC) injury may occur in the context predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, gerontologic), leading to metabolic dysfunction, senescence, aberrant activation, dysregulated repair. interacts with mesenchymal, immune, endothelial cells via multiple mechanisms trigger fibroblast myofibroblast activation. Recent single-cell RNA sequencing studies IPF lungs support model. These have uncovered novel type AEC characteristics an basal cell, which disrupt normal repair propagate profibrotic phenotype. Here, we review bioinformatics tools as strategies discover pathways disease, cell-specific mechanisms, cell-cell interactions that niche.

Language: Английский

Citations

432
SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis DOI Creative Commons
Daniel Wendisch, Oliver Dietrich, Tommaso Mari

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(26), P. 6243 - 6261.e27

Published: Nov. 27, 2021

Language: Английский

Citations

426
Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer DOI Creative Commons
Matthew B. Buechler, Wenxian Fu, Shannon J. Turley

et al.

Immunity, Journal Year: 2021, Volume and Issue: 54(5), P. 903 - 915

Published: May 1, 2021

Language: Английский

Citations

276
Transforming growth factor-β in myocardial disease DOI
Nikolaos G. Frangogiannis

Nature Reviews Cardiology, Journal Year: 2022, Volume and Issue: 19(7), P. 435 - 455

Published: Jan. 4, 2022

Language: Английский

Citations

195
TGF‐β as a driver of fibrosis: physiological roles and therapeutic opportunities DOI Open Access
Erine H. Budi,

Johanna Schaub,

Martin Decaris

et al.

The Journal of Pathology, Journal Year: 2021, Volume and Issue: 254(4), P. 358 - 373

Published: April 9, 2021

Many chronic diseases are marked by fibrosis, which is defined an abundance of activated fibroblasts and excessive deposition extracellular matrix, resulting in loss normal function the affected organs. The initiation progression fibrosis elaborated pro-fibrotic cytokines, most critical transforming growth factor-β1 (TGF-β1). This review focuses on fibrogenic roles increased TGF-β activities underlying signaling mechanisms fibroblast population other cell types that contribute to fibrosis. Insight into these as a universal driver has stimulated development therapeutic interventions attenuate progression, based interference with signaling. Their promise preclinical clinical settings will be discussed. © 2021 Pathological Society Great Britain Ireland. Published John Wiley & Sons, Ltd.

Language: Английский

Citations

171
RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field DOI Open Access
Beatrice Stefanie Ludwig, Horst Kessler, Susanne Kossatz

et al.

Cancers, Journal Year: 2021, Volume and Issue: 13(7), P. 1711 - 1711

Published: April 4, 2021

Integrins have been extensively investigated as therapeutic targets over the last decades, which has inspired by their multiple functions in cancer progression, metastasis, and angiogenesis well a continuously expanding number of other diseases, e.g., sepsis, fibrosis, viral infections, possibly also Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Although integrin-targeted (cancer) therapy trials did not meet high expectations yet, integrins are still valid promising due to elevated expression surface accessibility on diseased cells. Thus, for future successful clinical translation compounds, revisited innovative treatment strategies be explored based accumulated knowledge integrin biology. For this, refined approaches demanded aiming at alternative improved preclinical models, optimized selectivity pharmacological properties ligands, more sophisticated protocols considering dose fine-tuning compounds. Moreover, ligands exert accuracy disease monitoring diagnostic molecular imaging tools, enabling patient selection individualized therapy. The present review comprehensively analyzes state-of-the-art roles RGD-binding subtypes non-cancerous diseases outlines latest achievements design development synthetic application biomedical, translational, approaches. Indeed, substantial progress already made, including advanced ligand designs, numerous elaborated pre-clinical first-in-human studies, while discovery novel applications remains explored.

Language: Английский

Citations

164
Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis DOI Creative Commons
Yifan Tai, Emma L. Woods, Jordanna Dally

et al.

Biomolecules, Journal Year: 2021, Volume and Issue: 11(8), P. 1095 - 1095

Published: July 23, 2021

Myofibroblasts are contractile, α-smooth muscle actin-positive cells with multiple roles in pathophysiological processes. mediate wound contractions, but their persistent presence tissues is central to driving fibrosis, making them attractive cell targets for the development of therapeutic treatments. However, due shared cellular markers several other phenotypes, specific targeting myofibroblasts has long presented a scientific and clinical challenge. In recent years, have drawn much attention among research communities from disciplines specialisations. As further uncovers characterisations myofibroblast formation, function, regulation, realisation novel interventional routes within pathologies emerged. The community approaching means finally target these cells, prevent accelerate scarless healing, attenuate associated disease-processes settings. This comprehensive review article describes phenotype, origins, diverse physiological pathological functionality. Special been given mechanisms molecular pathways governing differentiation, updates interventions.

Language: Английский

Citations

159
The impact of the lung environment on macrophage development, activation and function: diversity in the face of adversity DOI Creative Commons
Calum C. Bain, Andrew S. MacDonald

Mucosal Immunology, Journal Year: 2022, Volume and Issue: 15(2), P. 223 - 234

Published: Jan. 11, 2022

The last decade has been somewhat of a renaissance period for the field macrophage biology. This renewed interest, combined with advent new technologies and development novel model systems to assess different facets biology, led major advances in our understanding diverse roles macrophages play health, inflammation, infection repair, dominance tissue environments influencing all these areas. Here, we discuss recent developments lung heterogeneity, ontogeny, metabolism function context health disease, highlight core conceptual key unanswered questions that believe should be focus work coming years.

Language: Английский

Citations

149
TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer DOI Creative Commons
Nancy R. Gough, Xiyan Xiang, Lopa Mishra

et al.

Gastroenterology, Journal Year: 2021, Volume and Issue: 161(2), P. 434 - 452.e15

Published: April 30, 2021

Genetic alterations affecting transforming growth factor-β (TGF-β) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator tissue renewal, TGF-β downstream SMAD-dependent transcriptional events play complex roles transition from noncancerous disease state to cancer tract, liver, pancreas. Furthermore, this pathway also regulates stromal cells immune system, which may contribute evasion tumors immune-mediated elimination. Here, we review involvement mediated by regulators SMADs progression digestive The integrates human genomic studies with animal models that provide clues toward understanding managing complexity cancer.

Language: Английский

Citations

146