The Role of the Stromal Extracellular Matrix in the Development of Pterygium Pathology: An Update

Pterygium is a benign fibrovascular lesion of the bulbar conjunctiva with frequent involvement of the corneal limbus. Its pathogenesis has been mainly attributed to sun exposure to ultraviolet-B radiation. Obtained evidence has shown that it is a complex and multifactorial process which involves multiple mechanisms such as oxidative stress, dysregulation of cell cycle checkpoints, induction of inflammatory mediators and growth factors, angiogenic stimulation, extracellular matrix (ECM) disorders, and, most likely, viruses and hereditary changes. In this review, we aim to collect all authors’ experiences and our own, with respect to the study of fibroelastic ECM of pterygium. Collagen and elastin are intrinsic indicators of physiological and pathological states. Here, we focus on an in-depth analysis of collagen (types I and III), as well as the main constituents of elastic fibers (tropoelastin (TE), fibrillins (FBNs), and fibulins (FBLNs)) and the enzymes (lysyl oxidases (LOXs)) that carry out their assembly or crosslinking. All the studies established that changes in the fibroelastic ECM occur in pterygium, based on the following facts: An increase in the synthesis and deposition of an immature form of collagen type III, which showed the process of tissue remodeling. An increase in protein levels in most of the constituents necessary for the development of elastic fibers, except FBLN4, whose biological roles are critical in the binding of the enzyme LOX, as well as FBN1 for the development of stable elastin. There was gene overexpression of TE, FBN1, FBLN5, and LOXL1, while the expression of LOX and FBLN2 and -4 remained stable. In conclusion, collagen and elastin, as well as several constituents involved in elastic fiber assembly are overexpressed in human pterygium, thus, supporting the hypothesis that there is dysregulation in the synthesis and crosslinking of the fibroelastic component, constituting an important pathogenetic mechanism for the development of the disease.

Download Full-text

Enhancement of elastin expression by transdermal administration of sialidase isozyme Neu2

Scientific Reports ◽

10.1038/s41598-021-82820-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Akira Minami ◽

Yuka Fujita ◽

Jun Goto ◽

Ayano Iuchi ◽

Kosei Fujita ◽

...

Keyword(s):

Sialic Acid ◽

Skin Diseases ◽

Lower Layer ◽

Elastic Fiber ◽

Sialic Acid Residue ◽

Elastic Fibers ◽

Transdermal Administration ◽

Sialidase Activity ◽

Fiber Assembly ◽

Senescence Accelerated Mice

AbstractReduction of elastin in the skin causes various skin diseases as well as wrinkles and sagging with aging. Sialidase is a hydrolase that cleaves a sialic acid residue from sialoglycoconjugate. Cleavage of sialic acid from microfibrils by the sialidase isozyme Neu1 facilitates elastic fiber assembly. In the present study, we showed that a lower layer of the dermis and muscle showed relatively intense sialidase activity. The sialidase activity in the skin decreased with aging. Choline and geranate (CAGE), one of the ionic liquids, can deliver the sialidase subcutaneously while maintaining the enzymatic activity. The elastin level in the dermis was increased by applying sialidase from Arthrobacter ureafaciens (AUSA) with CAGE on the skin for 5 days in rats and senescence-accelerated mice prone 1 and 8. Sialidase activity in the dermis was considered to be mainly due to Neu2 based on the expression level of sialidase isozyme mRNA. Transdermal administration of Neu2 with CAGE also increased the level of elastin in the dermis. Therefore, not only Neu1 but also Neu2 would be involved in elastic fiber assembly. Transdermal administration of sialidase is expected to be useful for improvement of wrinkles and skin disorders due to the loss of elastic fibers.

Download Full-text

Elastin exhibits a distinctive temporal and spatial pattern of distribution in the developing chick limb in association with the establishment of the cartilaginous skeleton

Journal of Cell Science ◽

10.1242/jcs.107.9.2623 ◽

1994 ◽

Vol 107 (9) ◽

pp. 2623-2634 ◽

Cited By ~ 1

Author(s):

J.M. Hurle ◽

G. Corson ◽

K. Daniels ◽

R.S. Reiter ◽

L.Y. Sakai ◽

...

Keyword(s):

Extracellular Matrix ◽

Spatial Pattern ◽

Elastic Fiber ◽

Spatial Location ◽

Limb Bud ◽

Confocal Laser ◽

Elastic Fibers ◽

Type I ◽

Temporal And Spatial

In this work we have analyzed the presence of elastic components in the extracellular matrices of the developing chick leg bud. The distributions of elastin and fibrillin were studied immunohistochemically in whole-mount preparations using confocal laser microscopy. The association of these constituents of the elastic matrix with other components of the extracellular matrix was also studied, using several additional antibodies. Our results reveal the transient presence of an elastin-rich scaffold of extracellular matrix fibrillar material in association with the establishment of the cartilaginous skeleton of the leg bud. The scaffold consisted of elastin-positive fibers extending from the ectodermal surface of the limb to the central cartilage-forming regions and between adjacent cartilages. Fibrillin immunolabeling was negative in this fibrillar scaffold while other components of the extracellular matrix including: tenascin, laminin and collagens type I, type III and type VI; appeared codistributed with elastin in some regions of the scaffold. Progressive changes in the spatial pattern of distribution of the elastin-positive scaffold were detected in explant cultures in which one expects a modification in the mechanical stresses of the tissues related to growth. A scaffold of elastin comparable to that found in vivo was also observed in high-density micromass cultures of isolated limb mesodermal cells. In this case the elastic fibers are observed filling the spaces located between the cartilaginous nodules. The fibers become reoriented and attach to the ectodermal basal surface when an ectodermal fragment is located at the top of the growing micromass. Our results suggest that the formation of the cartilaginous skeleton of the limb involves the segregation of the undifferentiated limb mesenchyme into chondrogenic and elastogenic cell lineages. Further, a role for the elastic fiber scaffold in coordinating the size and the spatial location of the cartilaginous skeletal elements within the limb bud is also suggested from our observations.

Download Full-text

Effects of chronic l-NAME treatment lung tissue mechanics, eosinophilic and extracellular matrix responses induced by chronic pulmonary inflammation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00199.2007 ◽

2008 ◽

Vol 294 (6) ◽

pp. L1197-L1205 ◽

Cited By ~ 29

Author(s):

Patrícia Angeli ◽

Carla M. Prado ◽

Débora G. Xisto ◽

Pedro L. Silva ◽

Caroline P. Pássaro ◽

...

Keyword(s):

Nitric Oxide ◽

Extracellular Matrix ◽

Smooth Muscle ◽

Lung Tissue ◽

Pulmonary Inflammation ◽

Elastic Fiber ◽

Tissue Mechanics ◽

Elastic Fibers ◽

Distal Lung ◽

Alveolar Septa

The importance of lung tissue in asthma pathophysiology has been recently recognized. Although nitric oxide mediates smooth muscle tonus control in airways, its effects on lung tissue responsiveness have not been investigated previously. We hypothesized that chronic nitric oxide synthase (NOS) inhibition by Nω-nitro-l-arginine methyl ester (l-NAME) may modulate lung tissue mechanics and eosinophil and extracellular matrix remodeling in guinea pigs with chronic pulmonary inflammation. Animals were submitted to seven saline or ovalbumin exposures with increasing doses (1∼5 mg/ml for 4 wk) and treated or not with l-NAME in drinking water. After the seventh inhalation (72 h), animals were anesthetized and exsanguinated, and oscillatory mechanics of lung tissue strips were performed in baseline condition and after ovalbumin challenge (0.1%). Using morphometry, we assessed the density of eosinophils, neuronal NOS (nNOS)- and inducible NOS (iNOS)-positive distal lung cells, smooth muscle cells, as well as collagen and elastic fibers in lung tissue. Ovalbumin-exposed animals had an increase in baseline and maximal tissue resistance and elastance, eosinophil density, nNOS- and iNOS-positive cells, the amount of collagen and elastic fibers, and isoprostane-8-PGF2α expression in the alveolar septa compared with controls ( P < 0.05). l-NAME treatment in ovalbumin-exposed animals attenuated lung tissue mechanical responses ( P < 0.01), nNOS- and iNOS-positive cells, elastic fiber content ( P < 0.001), and isoprostane-8-PGF2α in the alveolar septa ( P < 0.001). However, this treatment did not affect the total number of eosinophils and collagen deposition. These data suggest that NO contributes to distal lung parenchyma constriction and to elastic fiber deposition in this model. One possibility may be related to the effects of NO activating the oxidative stress pathway.

Download Full-text

Histological analysis of elastic cartilages treated with alkaline solution

Arquivo Brasileiro de Medicina Veterinária e Zootecnia ◽

10.1590/1678-4162-11539 ◽

2020 ◽

Vol 72 (3) ◽

pp. 647-654

Author(s):

K.D. Ferreira ◽

L.D. Cardoso ◽

L.P. Oliveira ◽

V.S. Franzo ◽

A. Pancotti ◽

...

Keyword(s):

Extracellular Matrix ◽

Alkaline Solution ◽

Histological Analysis ◽

Elastic Fiber ◽

Peripheral Region ◽

Cell Counting ◽

Elastic Fibers ◽

Fibrous Proteins ◽

Fibrous Protein ◽

Areas Of Interest

ABSTRACT The elastic cartilage is composed by chondroblasts and chondrocytes, extracellular matrix and surrounded by perichondrium. It has a low regeneration capacity and is a challenge in surgical repair. One of obstacles in engineering a structurally sound and long-lasting tissue is selecting the most appropriate scaffold material. One of the techniques for obtaining biomaterials from animal tissues is the decellularization that decreases antigenicity. In this work, alkaline solution was used in bovine ear elastic cartilages to evaluate the decellularization and the architecture of the extracellular matrix. The cartilages were treated in alkaline solution (pH13) for 72 hours and lyophilized to be compared with untreated cartilages by histological analysis (hematoxylin-eosin, Masson's trichrome and Verhoeff slides). Areas of interest for cell counting and elastic fiber quantification were delineated, and the distribution of collagen and elastic fibers and the presence of non-fibrous proteins were observed. The results demonstrated that the alkaline solution caused 90% decellularization in the middle and 13% in the peripheral region, and maintenance of the histological characteristics of the collagen and elastic fibers and non-fibrous protein removal. It was concluded that the alkaline solution was efficient in the decellularization and removal of non-fibrous proteins from the elastic cartilages of the bovine ear.

Download Full-text

Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils.

The Journal of Cell Biology ◽

10.1083/jcb.129.4.1165 ◽

1995 ◽

Vol 129 (4) ◽

pp. 1165-1176 ◽

Cited By ~ 207

Author(s):

H Zhang ◽

W Hu ◽

F Ramirez

Keyword(s):

Spatial Organization ◽

Developmental Stages ◽

Elastic Fiber ◽

Biomechanical Properties ◽

Developmental Expression ◽

Elastic Fibers ◽

Fiber Assembly ◽

Structural Support ◽

Functional Relationships ◽

Fibrillin 1

Extracellular microfibrils, alone or in association with elastin, confer critical biomechanical properties on a variety of connective tissues. Little is known about the composition of the microfibrils or the factors responsible for their spatial organization into tissue-specific macroaggregates. Recent work has revealed the existence of two structurally related microfibrillar components, termed fibrillin-1 and fibrillin-2. The functional relationships between these glycoproteins and between them and other components of the microfibrils and elastic fibers are obscure. As a first step toward elucidating these important points, we compared the expression pattern of the fibrillin genes during mammalian embryogenesis. The results revealed that the two genes are differentially expressed, in terms of both developmental stages and tissue distribution. In the majority of cases, fibrillin-2 transcripts appear earlier and accumulate for a shorter period of time than fibrillin-1 transcripts. Synthesis of fibrillin-1 correlates with late morphogenesis and the appearance of well-defined organ structures; fibrillin-2 synthesis, on the other hand, coincides with early morphogenesis and, in particular, with the beginning of elastogenesis. The findings lend indirect support to our original hypothesis stating that fibrillins contribute to the compositional and functional heterogeneity of the microfibrils. The available evidence is also consistent with the notion that the fibrillins might have distinct, but related roles in microfibril physiology. Accordingly, we propose that fibrillin-1 provides mostly force-bearing structural support, whereas fibrillin-2 predominantly regulates the early process of elastic fiber assembly.

Download Full-text

Effect of vaginal distention on elastic fiber synthesis and matrix degradation in the vaginal wall: potential role in the pathogenesis of pelvic organ prolapse

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90447.2008 ◽

2008 ◽

Vol 295 (4) ◽

pp. R1351-R1358 ◽

Cited By ~ 28

Author(s):

D. D. Rahn ◽

J. F. Acevedo ◽

R. A. Word

Keyword(s):

Pelvic Organ Prolapse ◽

Protease Activity ◽

Potential Role ◽

Elastic Fiber ◽

Pelvic Organ ◽

Vaginal Wall ◽

Elastic Fibers ◽

Wild Type ◽

Fiber Assembly ◽

Pregnant Mice

Matrix metalloprotease (MMP) activity is increased in the postpartum vagina of wild-type (WT) animals. This degradative activity is also accompanied by a burst in elastic fiber synthesis and assembly. The mechanisms that precipitate these changes are unclear. The goals of this study were to determine how vaginal distention (such as in parturition) affects elastic fiber homeostasis in the vaginal wall and the potential significance of these changes in the pathogenesis of pelvic organ prolapse. Vaginal distention with a balloon simulating parturition resulted in increased MMP-2 and MMP-9 activity in the vaginal wall of nonpregnant and pregnant animals. This was accompanied by visible fragmented and disrupted elastic fibers in the vaginal wall. In nonpregnant animals, the abundant amounts of tropoelastin and fibulin-5 in the vagina were not increased further by distention. In contrast, in pregnant animals, the suppressed levels of both proteins were increased 3-fold after vaginal distention. Distention performed in fibulin-5-deficient ( Fbln5−/−) mice with defective elastic fiber synthesis and assembly induced accelerated pelvic organ prolapse, which never recovered. We conclude that, in pregnant mice, vaginal distention results in increased protease activity in the vaginal wall but also increased synthesis of proteins important for elastic fiber assembly. Distention may thereby contribute to the burst of elastic fiber synthesis in the postpartum vagina. The finding that distention results in accelerated pelvic organ prolapse in Fbln5−/− animals, but not in WT, indicates that elastic fiber synthesis is crucial for recovery of the vaginal wall from distention-induced increases in vaginal protease activity.

Download Full-text

Elastin, arterial mechanics, and cardiovascular disease

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00087.2018 ◽

2018 ◽

Vol 315 (2) ◽

pp. H189-H205 ◽

Cited By ~ 32

Author(s):

Austin J. Cocciolone ◽

Jie Z. Hawes ◽

Marius C. Staiculescu ◽

Elizabeth O. Johnson ◽

Monzur Murshed ◽

...

Keyword(s):

Cardiovascular Disease ◽

Aortic Stenosis ◽

Autosomal Dominant ◽

Elastic Fiber ◽

Cutis Laxa ◽

Supravalvular Aortic Stenosis ◽

Elastic Fibers ◽

Arterial Mechanics ◽

Fiber Assembly

Large, elastic arteries are composed of cells and a specialized extracellular matrix that provides reversible elasticity and strength. Elastin is the matrix protein responsible for this reversible elasticity that reduces the workload on the heart and dampens pulsatile flow in distal arteries. Here, we summarize the elastin protein biochemistry, self-association behavior, cross-linking process, and multistep elastic fiber assembly that provide large arteries with their unique mechanical properties. We present measures of passive arterial mechanics that depend on elastic fiber amounts and integrity such as the Windkessel effect, structural and material stiffness, and energy storage. We discuss supravalvular aortic stenosis and autosomal dominant cutis laxa-1, which are genetic disorders caused by mutations in the elastin gene. We present mouse models of supravalvular aortic stenosis, autosomal dominant cutis laxa-1, and graded elastin amounts that have been invaluable for understanding the role of elastin in arterial mechanics and cardiovascular disease. We summarize acquired diseases associated with elastic fiber defects, including hypertension and arterial stiffness, diabetes, obesity, atherosclerosis, calcification, and aneurysms and dissections. We mention animal models that have helped delineate the role of elastic fiber defects in these acquired diseases. We briefly summarize challenges and recent advances in generating functional elastic fibers in tissue-engineered arteries. We conclude with suggestions for future research and opportunities for therapeutic intervention in genetic and acquired elastinopathies.

Download Full-text

Analysis of dermal elastic fibers in the absence of fibulin-5 reveals potential roles for fibulin-5 in elastic fiber assembly

Matrix Biology ◽

10.1016/j.matbio.2009.03.004 ◽

2009 ◽

Vol 28 (4) ◽

pp. 211-220 ◽

Cited By ~ 45

Author(s):

Jiwon Choi ◽

Andreas Bergdahl ◽

Qian Zheng ◽

Barry Starcher ◽

Hiromi Yanagisawa ◽

...

Keyword(s):

Elastic Fiber ◽

Elastic Fibers ◽

Fiber Assembly

Download Full-text

Role of LTBP4 in alveolarization, angiogenesis, and fibrosis in lungs

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00031.2017 ◽

2017 ◽

Vol 313 (4) ◽

pp. L687-L698 ◽

Cited By ~ 8

Author(s):

Insa Bultmann-Mellin ◽

Katharina Dinger ◽

Carolin Debuschewitz ◽

Katharina M. A. Loewe ◽

Yvonne Melcher ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Elastic Fiber ◽

Transforming Growth Factor Β ◽

Matrix Proteins ◽

Extracellular Matrix Protein ◽

Elastic Fibers ◽

Fiber Network

Deficiency of the extracellular matrix protein latent transforming growth factor-β (TGF-β)-binding protein-4 (LTBP4) results in lack of intact elastic fibers, which leads to disturbed pulmonary development and lack of normal alveolarization in humans and mice. Formation of alveoli and alveolar septation in pulmonary development requires the concerted interaction of extracellular matrix proteins, growth factors such as TGF-β, fibroblasts, and myofibroblasts to promote elastogenesis as well as vascular formation in the alveolar septae. To investigate the role of LTBP4 in this context, lungs of LTBP4-deficient ( Ltbp4−/−) mice were analyzed in close detail. We elucidate the role of LTBP4 in pulmonary alveolarization and show that three different, interacting mechanisms might contribute to alveolar septation defects in Ltbp4−/− lungs: 1) absence of an intact elastic fiber network, 2) reduced angiogenesis, and 3) upregulation of TGF-β activity resulting in profibrotic processes in the lung.

Download Full-text

Nanoindentation of histological specimens: Mapping the elastic properties of soft tissues

Journal of Materials Research ◽

10.1557/jmr.2009.0130 ◽

2009 ◽

Vol 24 (3) ◽

pp. 638-646 ◽

Cited By ~ 59

Author(s):

R. Akhtar ◽

N. Schwarzer ◽

M.J. Sherratt ◽

R.E.B. Watson ◽

H.K. Graham ◽

...

Keyword(s):

Mechanical Properties ◽

Extracellular Matrix ◽

Elastic Modulus ◽

Soft Tissues ◽

Elastic Fiber ◽

Vena Cava ◽

Elastic Fibers ◽

Fiber Density ◽

Tissue Microstructure ◽

Micromechanical Properties

Although alterations in the gross mechanical properties of dynamic and compliant tissues have a major impact on human health and morbidity, there are no well-established techniques to characterize the micromechanical properties of tissues such as blood vessels and lungs. We have used nanoindentation to spatially map the micromechanical properties of 5-μm-thick sections of ferret aorta and vena cava and to relate these mechanical properties to the histological distribution of fluorescent elastic fibers. To decouple the effect of the glass substrate on our analysis of the nanoindentation data, we have used the extended Oliver and Pharr method. The elastic modulus of the aorta decreased progressively from 35 MPa in the adventitial (outermost) layer to 8 MPa at the intimal (innermost) layer. In contrast, the vena cava was relatively stiff, with an elastic modulus >30 MPa in both the extracellular matrix-rich adventitial and intimal regions of the vessel. The central, highly cellularized, medial layer of the vena cava, however, had an invariant elastic modulus of ∼20 MPa. In extracellular matrix-rich regions of the tissue, the elastic modulus, as determined by nanoindentation, was inversely correlated with elastic fiber density. Thus, we show it is possible to distinguish and spatially resolve differences in the micromechanical properties of large arteries and veins, which are related to the tissue microstructure.

Download Full-text