|
 
 |
| REVIEW ARTICLE |
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| Year : 2019 | Volume
: 1
| Issue : 4 | Page : 117-126 |
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Galectin-3 and Fibrosis: Research in the Last 5 Years
Isaac Eliaz
Amitabha Medical Clinic and Healing Center, Santa Rosa, California, USA
| Date of Submission | 21-Nov-2019 |
| Date of Acceptance | 20-Aug-2020 |
| Date of Web Publication | 31-Dec-2020 |
Correspondence Address:
Dr. Isaac Eliaz
Amitabha Medical Clinic and Healing Center, 398 Tesconi Ct, Santa Rosa, California
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jtccm.jtccm_15_19
Tissue fibrosis is initially an adaptive response to organ injury, but eventually, parenchymal scarring and subsequent cellular dysfunction and organ failure ensue. Few therapies currently exist for fibrosis, especially those that target fibrogenesis. Galectin-3 (Gal-3) is a member of the lectin family of proteins, is produced predominantly by macrophages, and has essential functions in inflammation and angiogenesis. Gal-3 is activated in fibrotic models and abnormally elevated in fibrotic patients. Gal-3 inhibitors help to ameliorate or prevent fibrosis. For this review, we searched for original articles and reviews published between Jul 1, 2014, and Nov 1, 2019, using the following search terms (or combination of words) in PubMed: “galectin 3”, “fibrosis”, “heart”, “cardiac”, “liver”, “hepatic”, “lung”, “pulmonary”, “kidney”, and “renal”.
Keywords: Aldosterone, fibrosis, galectin-3, mineralocorticoid receptor antagonists
How to cite this article:
Eliaz I. Galectin-3 and Fibrosis: Research in the Last 5 Years. J Transl Crit Care Med 2019;1:117-26 |
| Introduction | |  |
Overview of fibrosis
Tissue fibrosis is the result of a cascade of cellular and molecular processes that originate from disease-related injury.[1] The fibrogenic response is adaptive initially, but over time, parenchymal scarring and subsequent cellular dysfunction and organ failure ultimately manifest. There are four major phases of the fibrogenic response.[1] First, primary injury to the organ causes initiation of the reaction. Activation of effector cells is the second phase, and the third phase is the elaboration of the extracellular matrix. These phases overlap with the fourth phase, where deposition (and inadequate resorption) of the extracellular matrix leads to the development of fibrosis and eventually end-organ failure.
There are common pathogenic pathways involved in the fibrotic changes in different organ systems. Specific molecular pathways are identified as underlying the “wounding response.” Inflammatory cells, epithelial cells, fibrogenic effector cells, endothelial cells, and others play important roles. Various effector cells function in fibrosis, including fibroblasts, myofibroblasts, cells originating from bone marrow, and cells originating from epithelial tissues. Specific core molecular pathways are vital, such as the transforming growth factor-beta (TGF-β) pathway.
During the development of fibrosis, myofibroblasts proliferate and sense physical and biochemical stimuli using integrins and cell-surface molecules, and mediators signal for pathological tissue contraction.[1] Organ deformation ensues, causing impairment in function. The specifics vary among organs. There are few therapies for fibrosis and fewer that specifically act on fibrogenesis. Thus, there is a need for further understanding of the pathogenesis of fibrogenesis to help discover new treatments.
Inflammation, both acute and chronic, can initiate fibrosis. Inflammation results in injury to the epithelial cells and often endothelial cells, leading to increased secretion of inflammatory mediators, such as cytokines, chemokines, and others. Various inflammatory cells are recruited, including lymphocytes, polymorphonuclear leukocytes, eosinophils, basophils, mast cells, and macrophages. These cells trigger effector cells[2] that push forward the fibrogenic process. Macrophages may also participate in interstitial fibrosis, often along the TGF-β pathway.[3]
Fibroblasts and myofibroblasts promote the formation of extracellular matrix proteins in fibrosis.[4] The fibrotic scar formed by highly conserved matrix proteins consists mostly of interstitial collagens (Types I and III), cellular fibronectin, basement-membrane proteins such as laminin, and other, less abundant elements.[1] Further, myofibroblasts are contractile;[5] when these cells contract, they deform parenchymal structure, leading to disease pathogenesis and tissue failure.
The molecular systems underlying fibrosis are too expansive to allow for detailed discussion. Platelet-derived growth factor, connective tissue growth factor, and vasoactive peptide systems (especially angiotensin II and endothelin-1)[6] have prominent roles. In vasoactive systems, endothelin participates in fibrosis in nearly every organ, acting through G-protein-coupled endothelin-A or endothelin-B cell-surface receptors or both.[7] In addition, angiogenic pathways may be critical in fibrosis.[8] Integrins, which link extracellular matrix to the cells, are also crucial in the pathogenesis of fibrosis.[9],[10]
Abrogation of injury and inflammatory responses leads to resorption of extracellular matrix proteins, which promotes organ repair. However, when a chronic injury does not subside, the continuous activation of effector cells leads to repeated deposition of the extracellular matrix, progressive scarring, and organ damage. Therefore, fibrogenesis involves the give-and-take among factors promoting biosynthesis, deposition, and degradation of extracellular matrix proteins. In typical situations, matrix synthesis counterbalances with matrix-degrading metalloproteases.[11],[12],[13] Furthermore, some antifibrogenic pathways act by removing effectors (e.g., through senescence, apoptosis, or autophagy). One example is the association of apoptosis of hepatic stellate cells with the reversal of fibrosis.[14]
Galectin-3
Galectin-3 (Gal-3) is a member of the lectin family of proteins, which recognizes and binds to specific carbohydrate motifs on glycosylated proteins as well as lipids.[15] Gal-3 is produced predominantly by macrophages and has important functions in inflammation and angiogenesis.[16],[17]
Gal-3 is widely expressed in the human tissues, including all types of immune cells (macrophages, monocytes, dendritic cells, eosinophils, mast cells, natural killer cells, and activated T- and B-cells), epithelial cells, endothelial cells, and sensory neurons.[18],[19] The Gal-3 expression is increased during embryogenesis as compared to adult life.[20] Nonetheless, Gal-3-knockout mice can survive with few limitations, except for early senescence.[21]
Gal-3 is mainly located in the cytoplasm and shuttles into the nucleus.[18] It can also migrate to the cell surface and into biological fluids.[22] The various functions of Gal-3 are largely determined by its different locations.[18] For instance, Gal-3 promotes survival in the cytoplasm as a result of its interaction with certain survival-associated proteins, such as B-cell lymphoma-2 (BCL2) and activated guanosine-5′-triphosphate-bound K-Ras. In the nucleus, Gal-3 functions in pre-mRNA splicing and gene transcription. Extracellular Gal-3 affects cell–cell interactions, such as those between epithelial cells and the extracellular matrix. This entails that Gal-3 has an important role in cell differentiation, inflammation, fibrogenesis, and the host.[22],[23] Earlier research demonstrates that Gal-3 is involved in cardiovascular remodeling, in addition to several autoimmune and inflammatory processes.[19],[20],[24],[25],[26],[27],[28],[29],[30]
A review of studies published before July 2014 demonstrated that Gal-3 is activated in the fibrotic models and is abnormally elevated in fibrotic patients. Furthermore, Gal-3 inhibitors help to ameliorate or prevent fibrosis.[31] In the present review, we mainly focused on the literature published from July 2014 to update the role of Gal-3 in fibrotic diseases, specifically cardiac, hepatic, pulmonary, and renal.
| Methods | | |
Search strategy and selection criteria
We searched for original articles and reviews published between July 1, 2014, and November 1, 2019, using the following search terms (or combination of words) in PubMed: “Gal-3,” “fibrosis,” “heart,” “cardiac,” “liver,” “hepatic,” “lung,” “pulmonary,” “kidney,” and “renal.” We excluded articles that focused on skin healing because this was covered in a recent review and because the mechanisms of skin remodeling appear to be different, when compared to remodeling of heart, liver, lung, and kidney.[32] The inclusion criteria consisted of only full-text articles written in English. Articles in journals with stringent peer-review processes were favored.
| Results | | |
The results are presented in [Table 1].
| Discussion | | |
Galectin-3 in fibrotic diseases
Galectin-3 in cardiac fibrosis
Protein kinase C (PKC)-α promotes cardiac fibrosis and heart failure (HF) by the stimulation of Gal-3 expression.[33] Activation of Gal-3 expression in the atria can subsequently activate the TGF-β1/α-smooth muscle actin/collagen I (Col I) pathway in cardiac fibroblasts, which may enhance atrial fibrosis.[34] Cardiotrophin-1 (CT-1) upregulates Gal-3, which, in turn, mediates the pro-inflammatory and pro-fibrotic myocardial effects of CT-1.[35] An inverse association is observed between myocardial Gal-3 expression and cardiac fibrosis in patients with inflammatory cardiomyopathy, but in patients with dilated cardiomyopathy, myocardial Gal-3 expression is positively correlated with cardiac fibrosis on left ventricular (LV) biopsy.[36] Reduction of coxsackievirus B3-induced cardiac damage and inflammatory responses, through the inhibition of Gal-3, may be achieved with the subsequent decrease of chronic fibrosis.[37] Inhibition of Gal-3 and aldosterone (Aldo) can reverse isoproterenol-induced LV dysfunction by reducing myocardial inflammation and fibrogenesis.[38] Modulation of Gal-3 and interleukin (IL)-33/ST2 signaling induced by mineralocorticoid receptor antagonists (MRAs) correlates with lower expression levels of fibrosis and inflammatory markers.[39] Perindopril and PectaSol-C Modified Citrus Pectin (P-MCP, ecoNugenics, Santa Rosa, CA, USA) comparably improve ischemic HF in rabbits, by downregulating Gal-3 and reducing myocardial fibrosis.[40] In obese animals, the Gal-3 blockade with P-MCP decreases cardiovascular fibrosis and inflammation.[41] Gal-3 pharmacological inhibition using P-MCP improves cardiac fibrosis associated with ischemia/reperfusion (IR).[42] P-MCP treatment prevents the increase in Gal-3, media thickness, fibrosis, and inflammation in the aorta of pressure overload (PO) rats.[43]
Galectin-3 in hepatic fibrosis
The first-in-human, Phase 1 clinical trial in patients with histologically confirmed nonalcoholic steatohepatitis (NASH) and advanced fibrosis demonstrates that the Gal-3 pharmacological inhibitor GR-MD-02 is safe and well tolerated.[44] dnTGF-βRII/Gal-3-/-(dn/Gal3-/-) mice were generated to confirm the critical role of Gal-3 in the pathogenesis of cholestatic liver injury, which showed impaired inflammasome activation along with significantly improved inflammation and fibrosis.[45] P-MCP attenuated liver fibrosis through an antioxidant effect, and the inhibition of Gal-3 mediated hepatic stellate cells' activation and induction of apoptosis.[46] Gal-3 attenuates steatosis but promotes liver injury, inflammation, and fibrosis in an obesogenic mouse model of NASH, thus demonstrating the involvement of Gal-3 in the progression of NASH. Further, the pro-fibrogenic IL-33/ST2/IL-13 pathway is Gal-3 dependent.[47]
Galectin-3 in pulmonary fibrosis
Gal-3 contributes to the exaggerated injury and fibro-proliferative repair responses in Hermansky–Pudlak syndrome (HPS) by altering the anti-apoptotic and fibro-proliferative effects of chitinase 3-like 1 and its receptor complex in a tissue compartment-specific manner.[48] In pulmonary adventitial fibroblasts, the necessity of Gal-3 to stimulate TGF-β1-vascular fibrosis via a STAT3 signaling cascade is proven.[49] Gal-3-antagonists and a selective galactose-coumarin-derived Gal-3 inhibitor attenuate bleomycin-induced pulmonary fibrosis in mouse models.[50] Elevated Gal-3 concentrations are associated with interstitial lung abnormalities coupled with a restrictive pattern, including decreased lung volumes and altered gas exchange, thus suggesting a potential role for Gal-3 in the early stages of pulmonary fibrosis.[51] In addition, abnormal accumulation of Gal-3 may contribute to the pathogenesis of HPS pulmonary fibrosis.[52]
Galectin-3 in renal fibrosis
Gal-3 inhibition is a viable strategy for alleviating acute kidney injury (AKI) and chronic kidney disease transition induced by cisplatin mediated by the reduction of cell apoptosis and attenuation of Col I and fibronectin.[53] Gal-3 inhibition also suppresses PKC-α. Gal-3 inhibition attenuates early renal damage in spontaneously hypertensive rats (SHRs) as indicated by reduced albuminuria, improved renal function, and decreased renal fibrosis, epithelial–mesenchymal transition molecules, and inflammation, independently of blood pressure levels.[54] In experimental models of mild kidney damage, the increase in renal Gal-3 expression paralleled with renal fibrosis, inflammation, and organ damage, all of which were prevented by Gal-3 blockade.[55] In experimental hyperaldosteronism, the increase in Gal-3 expression is associated with renal fibrosis and dysfunction but is stopped by inhibition with P-MCP or genetic disruption of Gal-3.[56] AKI induces remote cardiac dysfunction, damage, injury, and fibrosis via a Gal-3–dependent pathway, and Gal-3 originates from bone marrow-derived immune cells in this model.[57]
Mechanisms of galectin-3 in fibrosis
Anti-apoptosis
Gal-3 often serves an anti-apoptotic function.[58],[59] It affects several different signal transduction cascades and pro-survival processes, including Ras, BCL2, and MYC.[58],[59] For instance, the suppression of Gal-3's anti-apoptotic function appears to be important for treating some cancer cells.[25] Gal-3 regulates BCL2 and other BCL2 family members through direct binding.[58],[59] Further, lowering Gal-3 has been shown to reduce BCL2 protein levels.[60] Gal-3 regulates a survival axis in acute myeloid leukemia (AML) cells, which may be targeted via combined inhibition with drugs such as GCS-100 and ABT-199.[61] Gal-3 knockdown inhibits cell proliferation and invasion, induces caspase-3-dependent apoptosis, and arrests cell cycle at G1 phase.[62] Gal-3 deficiency increases susceptibility to cisplatin-induced apoptosis, while the administration of recombinant Gal-3 attenuates cisplatin-induced AKI in Gal-3-knockout mice by preventing Bax and caspase-3-dependent apoptosis.[63] Moreover, P-MCP attenuates cisplatin-induced AKI by suppressing PKC-α-driven apoptosis.[53] Use of novel-specific Gal-3 inhibitor CBP. 001 in co-culture of AML cells with mesenchymal stromal cells reduced viable leukemia cell populations with induced apoptosis and augmented the chemotherapeutic effect of cytosine arabinoside (ara-C), a chemotherapeutic agent commonly used in the treatment of leukemia and lymphomas.[64]
Cell adhesion and migration
Gal-3 can bind to many molecules that affect cell adhesion, such as integrins, cadherins, and other cell surface glycoproteins.[65],[66],[67],[68],[69] Gal-3 can complex with integrins or other cell surface proteins (e.g., MUC-1) to propagate signaling pathways that lead to cell adhesion of tumor cells to stromal cells and promote survival signaling cascades.[65],[66],[69],[70] Gal-3 can form pentamers with glycoproteins (or glycolipids), which enables it to organize molecules on the surface of the plasma membrane. This is performed along with other proteins on the extracellular surface of the plasma membrane (e.g., fibronectin and integrins) as well as proteins that reside in the intracellular side of the plasma membrane.[25] Gal-3 binds to glycoproteins (as well as glycolipids) to form lattices that organize these proteins at the extracellular plasma membrane surface. The number of glycans contained on a glycoprotein will determine its binding to Gal-3 and therefore will affect the composition of these lattices.[25] Kinase receptors such as TCR and CD44, integrins, and other proteins bind to Gal-3 and the composition of the lattice that is formed also depends on MGAT5-mediated effects.[68],[69] Regulation of Gal-3 gene expression by the integrin also offers feedback regulation of cell adhesion/motility.
Angiogenesis
Gal-3 has been reported as a pro-angiogenic molecule that is triggered during hypoxia[30] and increases the chemotaxis and differentiation of the human umbilical vein endothelial cells by enhancing vascular endothelial growth factor (VEGF) receptor-2 signaling activation.[71] Disruption of Gal-3 in the tumor stroma lowers macrophage-induced angiogenesis dependent on VEGF and TGF-β signaling.[72] Further, under hypoxic conditions, Gal-3 is released by cancer cells and preferentially binds to endothelial cells – themselves induced – to increase binding by hypoxia. Upon binding to endothelial cells, Gal-3 triggers angiogenic sprouting by promoting Jagged-1/Notch signaling activation.[73] Targeting Gal-3 by the novel, small-molecule inhibitor, 33DFTG, ameliorates pathological corneal angiogenesis as well as fibrosis.[74] In addition, a blocker of endogenous Gal-3 significantly reduces the growth, motility, invasion, and angiogenic potential of cultured ovarian cancer (OC) cell lines and primary cells established from OC patients.[75] Furthermore, 2- or 6-de-O-sulfated, N-acetylated heparin derivatives are Gal-3 binding inhibitors. These chemically modified heparin derivatives inhibit Gal-3-ligand binding and abolish Gal-3-mediated cancer cell-endothelial adhesion and angiogenesis.[76] The role of Gal-3 in angiogenesis is likely tissue and context dependent.[77]
Inflammation and oxidative stress
The fibrotic effects of Gal-3 are due to its ability to bind matrix proteins such as cell surface receptors (integrins), collagen, elastin, and fibronectin.[78] Gal-3 transforms quiescent fibroblasts into myofibroblasts that manufacture and secrete matrix proteins, such as collagens.[79],[80] In addition to collagen production, Gal-3 is involved in collagen maturation, externalization, and cross-linking. Triggering of pro-inflammatory molecules is another mechanism by which Gal-3 promotes fibrosis.[81] For instance, in human cardiac fibroblasts, Gal-3 augments the formation and the secretion of IL-1 β, IL-6, monocyte chemoattractant protein-1 (CCL-2), collagen Type I, collagen Type III, and fibronectin as well as the activity of matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9.[82]
New data suggest that Gal-3 is also involved in reactive oxygen species (ROS) generation. Gal-3 plays an important role in pulmonary arterial hypertension (PAH)-induced right ventricular remodeling through interacting with the NADPH oxidase 4 and Nox4-derived oxidative stress.[83] Furthermore, Gal-3 decreases the peroxiredoxin-4 antioxidant system in the cardiac fibroblasts, increasing oxidative stress.[84] Moreover, Gal-3 downregulates fumarate hydratase, thereby increasing fumarate production in human cardiac fibroblasts, which causes increased ROS levels and increased collagen production.[43]
Aldosterone/mineralocorticoid receptor activation
Blockade of mineralocorticoid receptor (MR) stimulation (by an MRA) starkly lowers fibrosis.[85] Mechanistic studies show that Gal-3 especially mediates cardiovascular and renal fibrosis in the pathological conditions related to high Aldo levels [Figure 1].[41],[56],[82],[86],[87] Furthermore, hyperaldosteronism exacerbates hypertension-induced cardiovascular fibrosis by increasing Gal-3.[88] | Figure 1: Galectin-3 mediates the fibrotic effects of hyperaldosteronism. Aldosterone causes galectin-3 expression and release. The abrogation of these effects of aldosterone-induced fibrosis seen with genetic silencing or pharmacological inhibition of galectin-3
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Aldosterone/mineralocorticoid receptor regulates galectin-3 expression in vitro
In primary cultured vascular smooth muscle cells (VSMCs), Aldo was found to increase Gal-3 expression dose and time dependently via its MR.[86] Gal-3, via its lectin activity, is a necessary mediator allowing Aldo-induced collagen Type I synthesis, because the blockade of Gal-3 with carbohydrates such as P-MCP or N-acetyl-D-lactosamine abolishes Aldo-induced collagen Type I deposition. In addition, Gal-3-depleted VSMCs do not develop fibrosis in response to Aldo, including a lack of collagen Type I deposition.[86]
In the human cardiac fibroblasts, Aldo also increased Gal-3 expression via its MR, and Gal-3 and Aldo augment pro-inflammatory and pro-fibrotic markers, as well as metalloproteinase activities.[82] Gal-3-silenced cells treated with Aldo did not present these effects. In support of the above, Aldo induced Gal-3 secretion in the inflammatory cells through MR and via PI3K/Akt and NF-kB transcription signaling pathways, amplifying the inflammatory response.[89]
Galectin-3 in clinical populations
Gal-3 levels are elevated in a cohort of patients with Aldo-producing adenoma. One year after adrenalectomy, plasma Gal-3 levels decrease, corroborating the findings in mechanistic studies.[89] However, another study found that Gal-3 levels are not increased in patients with primary hyperaldosteronism, and Gal-3 levels do not decrease after adrenalectomy.[90] As a biomarker, increased or increasing Gal-3 may identify patients with excessive risk for poor outcomes, signifying a rapid form of HF with progressive remodeling.[91]
In untreated congestive HF, Aldo levels are increased in proportion to the severity of the disease and are further increased by the use of diuretic treatment.[92] Serum Gal-3 level is associated with the serum markers of cardiac extracellular matrix turnover in HF patients, suggesting that Gal-3 could be a biomarker of HF onset, morbidity, and mortality.[93]
In morbidly obese patients presenting high Aldo levels, insulin resistance, and LV hypertrophy, high Gal-3 levels are associated with worse diastolic function.[41] Furthermore, in patients with aortic stenosis (AS), cardiac Gal-3 is elevated and associated with markers of myocardial fibrosis and inflammation.[94] Aldo and Gal-3 are both increased in PAH patients. Further, plasma levels of both molecules are associated with PAH severity.[95] Gal-3 is also positively associated with Nox4 in PAH patients.[83]
Given the connection between Aldo, Gal-3, and cardiovascular fibrosis, the predictive value of Gal-3 in patients treated with MRAs was examined. MRA treatment does not alter the prognostic value of Gal-3 in HF patients.[96] In addition, no evidence was seen of interaction between the Gal-3 level and treatment effect of MRA.[97] Finally, among patients with chronic HF and elevated Gal-3 concentrations, there is no benefit from the addition or intensification of MRA therapy.[98]
| Conclusion | | |
Many studies observe increased Gal-3 levels in patients with fibrosis affecting different tissues.[99],[100],[101] Studies that examined the pathogenic role of Gal-3 in fibrosis identified Gal-3 as the link between macrophages, fibroblasts, and pro-fibrotic phenotype. These observations have led to the concept of a Gal-3/macrophage/fibroblast “axis” [Figure 2]. Many results suggest that Gal-3 is a useful new simple biomarker in the prediction of disease related to the heart, liver, lung, or kidney and mortality associated with these diseases. Its inhibition represents a promising therapeutic strategy against tissue fibrosis. | Figure 2: The galectin-3/macrophage/fibroblast axis. Galectin-3 promotes fibrosis through multiple mechanisms. It activates fibroblasts directly, and also via syndecans and TGF-β. It also induces alternative activation in macrophages. Finally, galectin-3 reduces apoptosis of neutrophils, thereby leading to increased inflammation and subsequent fibrosis. TGFβ: Transforming growth factor-beta; TGFβR: Transforming growth factor-beta receptor
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Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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