Cellular and Molecular Genetic Mechanisms of Lung Fibrosis Development and the Role of Vitamin D: A Review
Abstract
:1. Introduction
2. Key Pathogenetic Mechanisms and Cell Populations in the Development of Pulmonary Fibrosis
2.1. Alveolar Epithelium
2.2. Cells of the Stromal Microenvironment—Fibroblasts, Myofibroblasts, and Vascular Endothelium
2.3. Immunocompetent Cells
2.4. Cell Aging and Apoptosis
3. Effects of Vitamin D and Its Analogues Implemented through Ligand-Associated Activation of Vitamin D Receptors
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
Abbreviation | Full Name |
EMT | Epithelial–mesenchymal transition |
FGFR | Fibroblast growth factor receptor |
IFN-γ | Interferon gamma |
IL | Interleukin |
IPF | Idiopathic pulmonary fibrosis |
LXR | Liver X-receptor |
M1 | Macrophage type 1 |
M2 | Macrophage type 2 |
miRNA | Micro RNA |
MMP | Metalloproteinase |
PAI | Plasminogen activator inhibitor |
PDGFR | Platelet-derived growth factor receptor |
RAS | Renin–angiotensin system |
RXR | Retinoic acid receptors |
SASP | Senescence-associated secretory phenotype |
TGF-β | Transforming growth factor beta |
Th1 | T-helper type 1 |
Th17 | T-helper type 17 |
Th2 | T-helper type 2 |
Th9 | T-helper type 9 |
TNF-α | Tumor necrosis factor alpha |
Treg | Regulatory T-cell |
VDR | Vitamin D receptor |
VEGFR | Vascular endothelial growth factor receptor |
Vit D | Vitamin D |
α-SMA | Alpha-smooth muscle actin |
γδT cells | Gamma delta T-cell |
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Drug | Target | Study Design, Phase, and Number of Participants | Summary of Main Findings | Name and Status of Clinical Trial (NCT) |
---|---|---|---|---|
Pirfenidone | TGF-β | Randomized, double-blind, placebo-controlled, parallel-group study; Phase 3; in total, 779 patients with IPF | Positive dose-dependent effect with reduced decline in FVC vs. placebo and favorable benefit risk profile [18] | CAPACITY, completed (NCT00287729, NCT00287716) |
Randomized, double-blind, placebo-controlled, parallel-group study; Phase 3; 555 patients with IPF | Reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival [19] | ASCEND, completed (NCT01366209) | ||
Open-label extension study; Phase 3; 1058 patients with IPF | Mean change in percent predicted FVC from baseline at 180 weeks was −9.6%; median on-treatment survival from the first pirfenidone dose was 77.2 months [20] | RECAP, completed (NCT00662038) | ||
BG00011 (anti-αvβ6 monoclonal antibody) | TGF-β/TGF-β receptors—integrins αV/β6 | Randomized, double-blind, placebo-controlled, parallel-group study; Phase 2; 109 patients with IPF | Early trial termination due to imbalance in adverse events and lack of clinical benefit [21] | SPIRIT, terminated (NCT03573505) |
PLN-74809 (Bexotegrast) | TGF-β/TGF-β receptors—integrins αV/β1, αV/β6 | Randomized, double-blind, dose-ranging, placebo-controlled, parallel-group study; Phase 2a; 120 patients with IPF | Dose-dependent antifibrotic effect (reduction in FVC decline over 12 weeks vs. placebo) [22] | INTEGRIS-IPF, completed (NCT04396756) |
Nintedanib | Tyrosine kinases (VEGFR 1–3, FGFR 1–3, PDGFR α, β) | Randomized, double-blind, dose-ranging, placebo-controlled, parallel-group study; Phase 3; 663 patients with progressive fibrosing interstitial lung disease | Slower rate of progression of the interstitial lung disease (reduction in FVC decline) [23] | INBUILD, completed (NCT02999178) |
Pamrevlumab | CTGF | Randomized, double-blind, placebo-controlled, parallel-group study; Phase 3; in total, 728 patients with IPF | Termination of a planned open-label extension study of pamrevlumab as well as the ongoing ZEPHYRUS-2 trial due to a lack of effectiveness [24] | ZEPHYRUS-1,2, terminated (NCT03955146, NCT04419558) |
Signaling Pathway | Signaling Pathway Inductor | The Implemented Cascade of Reactions | Effect of Vit D Complex/VDR |
---|---|---|---|
SMAD | TGF-β/receptors TGF-β; angiotensin II | Regulation of cellular cycle, differentiation (in particular of myofibroblasts), immune reactions | Suppression by reducing TGF-β expression and nuclear translocation of SMAD components |
MARK | TGF-β, growth factors, lipopolysaccharides, etc. | Regulation of cellular proliferation and differentiation, inflammatory response, and elimination of cells by apoptosis | Suppression by enhancing the expression of proteinase (MAPK phosphatase-1) followed by inhibition of p38 MAPK |
NF-κβ | Proinflammatory cytokines (IL-1 and TNF-α), lipopolysaccharides, and growth factors | Regulation of non-specific and adaptive immunity and inflammatory response | Suppression by inhibiting Ikkß kinase and preventing activation of NF-kß, as well as by suppressing nuclear translocation of signaling pathway components |
JAK/STAT | Cytokines (IL-2, IL-6, IL-10, IL-12, IFN-α, etc.) and growth factors (EGF) | Regulation of cellular proliferation, differentiation, and inflammatory response | Suppression of binding of transcription factor STAT3 to the promoter (ATF6) |
PPAR-α/γ | Unsaturated fatty acids, eicosanoids, etc. | Regulation of metabolism of fatty acids and energy balance, regulation of immune response, and cellular cycle | Competitive interaction due to binding to RXR and suppression of the PPAR-α/γ promoter |
NFAT | Ca2+ | Regulation of cellular cycle and inflammatory response | Blocking of NFAT components of Runx1 transcription factor |
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Enzel, D.; Kriventsov, M.; Sataieva, T.; Malygina, V. Cellular and Molecular Genetic Mechanisms of Lung Fibrosis Development and the Role of Vitamin D: A Review. Int. J. Mol. Sci. 2024, 25, 8946. https://doi.org/10.3390/ijms25168946
Enzel D, Kriventsov M, Sataieva T, Malygina V. Cellular and Molecular Genetic Mechanisms of Lung Fibrosis Development and the Role of Vitamin D: A Review. International Journal of Molecular Sciences. 2024; 25(16):8946. https://doi.org/10.3390/ijms25168946
Chicago/Turabian StyleEnzel, Darya, Maxim Kriventsov, Tatiana Sataieva, and Veronika Malygina. 2024. "Cellular and Molecular Genetic Mechanisms of Lung Fibrosis Development and the Role of Vitamin D: A Review" International Journal of Molecular Sciences 25, no. 16: 8946. https://doi.org/10.3390/ijms25168946