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PubMed1998

Conjugated equine estrogens alone, but not in combination with medroxyprogesterone acetate, inhibit aortic connective tissue remodeling after plasma lipid lowering in female monkeys.

The objective of this study was to determine the arterial responses to plasma lipid lowering alone or in combination with (1) estrogen replacement therapy or (2) hormone replacement therapy in surgically postmenopausal female monkeys with preexisting atherosclerosis. Eighty-eight female cynomolgus macaques were ovariectomized, fed an atherogenic diet for 24 months, and then assigned by randomized stratification into 4 groups. One group (baseline, n=20) was necropsied at the end of the atherogenic diet period; the remaining 3 groups were fed a plasma lipid-lowering diet (regression) for 30 months. These regression groups were control (diet only), CEE (receiving conjugated equine estrogens alone), and CEE+MPA (receiving CEE and continuous medroxyprogesterone acetate). A previous report described coronary artery functional and histological results; the present report describes biochemical and histological results from the abdominal aorta. Aortic plaque size was not different between groups, similar to previous findings in the coronary arteries. Aortic cholesterol content (milligrams per gram lipid-free dry weight) was lower in the regression groups compared with baseline, both for free cholesterol (mean, control=19.1, CEE=15.7, CEE+MPA=14.4, and baseline=32.7; P<0.001) and for esterified cholesterol (mean, control=18.9, CEE=15.4, CEE+MPA=14.2, and baseline=58.7; P<0.001). This cholesterol efflux could lead to increased plaque stability without changing the physical size of the lesion. Alterations in aortic connective tissue composition were observed in the regression groups. When expressed as a percentage of the lipid-free tissue weight, the aortic elastin content of the control (mean=14.9) and the CEE+MPA (mean=14.0) groups was lower than that of the baseline group (mean=19.0), which was not different from that of the CEE group (mean=15.8). Aortic collagen content, as estimated by hydroxyproline content per milligram of lipid-free tissue, was higher in the control group (mean=67.4) and the CEE+MPA group (mean=66.1) than in the baseline group (mean=56.2; P<0.05). Collagen content of the CEE group (mean=58.9) was not different from that of the baseline group. When the regression groups were considered separately, the aortic collagen content of the CEE group was lower than that of the control group (P<0.05) and tended to be lower than that of the CEE+MPA group (P=0.10), suggesting that CEE therapy (but not CEE+MPA) inhibits potentially detrimental connective tissue alterations that accompany lesion regression. These results have implications for combinations of lipid-lowering and hormone replacement therapies in relation to vascular remodeling and abdominal aortic aneurysm development.

Animals↗

PubMed2004

A novel approach for preventing esophageal stricture formation: sphingosylphosphorylcholine-enhanced tissue remodeling.

Using a new class of intracellular 2nd messengers to prevent stricture formation after caustic ingestion, sphingosylphosphorylcholine (SPC) has a wide spectrum of activity in cell growth regulation and signal transduction. Caustic esophageal burns were created with 15% NaOH in an experimental rat model. Control group animals (n = 10) had esophageal burns with no treatment, whereas the SPC group (n = 10) had esophageal burns gavaged with SPC for 7 days. Efficacy of treatment was assessed in 28 days by contrast esophagograms, histopathologic evaluation, and biochemically by tissue hydroxyproline (OHP) content. Contrast esophagograms demonstrated that SPC significantly prevented stricture formation. Obvious collagen deposition was present in submucosa, muscularis mucosa, and muscular layers in the control group compared with the SPC group. The damage to the esophageal wall on histopathologic examination was significantly lower in the SPC group (p < 0.05). Tissue OHP contents were significantly lower in the SPC-treated group (3.0 +/- 0.1 microg/mg) compared with the control group (4.3 +/- 0.2 microg/mg) (p < 0.05). We conclude that SPC improves healing following caustic esophageal burns. Furthermore, SPC is effective in preventing caustic esophageal strictures. These effects of SPC occur through its proliferative and specifically its remodeling effects on wound healing.

Animals↗

PubMed1999

Molecular and cellular basis of tissue remodeling during amphibian metamorphosis.

Amphibian metamorphosis involves systematic transformations of various tadpole organs/tissues. Three major types of changes take place during this process. These are remodeling, resorption, and de novo development, all of which appear to involve both cell proliferation and apoptosis (programmed cell death). All metamorphic changes are controlled by thyroid hormone (T3) and are organ-autonomous. Recent studies using primary cell cultures and a stably transformed cell line from tadpole tissues have implicated that T3 induces apoptosis cell-autonomously. This T3-induced, metamorphosis-associated apoptosis is similar to cell death in other animal species and involves similar cell death executioners. Both the activation of these executioners and the pathways leading to cell proliferation and differentiation are believed to be through transcriptional regulation by T3 receptors (TRs). TRs can activate or repress target gene transcription depending upon the presence or absence of T3, respectively. Many direct T3-response genes have been isolated and found to encode a variety of proteins that can affect both intra- and extra-cellular events. The determinations of the identities of these response genes through sequence analyses and studies on their expression profiles during development have provided strong clues toward their roles in metamorphosis. However, future studies using organ and cell culture systems and/or transient or stable transgenic technologies are required to understand how these genes transduce the T3 signal to activate the downstream cell death and proliferation/differentiation pathways.

Amphibians↗

PubMed2006

Fibrogenic cell fate during fibrotic tissue remodelling observed in rat and human cultured liver slices.

BACKGROUND/AIMS: Fibrotic liver remodelling was studied in culture of precision-cut liver slices (PCLS) derived from fibrotic liver. METHODS: Fibrosis was induced in rats by carbon tetrachloride (CCl4) treatment or bile duct ligation. Human fibrotic livers were also used. PCLS were cultured for 6, 24, 48, or 72 h, and the expression of alpha-smooth muscle (SM) actin, platelet-derived growth factor (PDGF) receptor-beta, and active caspase 3 was studied by immunohistochemistry. RESULTS: Before culture, in CCl4-treated or bile duct ligated animals, fibrosis was observed around centrolobular veins, or in portal zones, respectively. In PCLS derived from CCl4-treated animals, alpha-SM actin expression disappeared after 24h in culture while PDGF receptor-beta expression decreased progressively after 48 h. These changes were observed in absence of massive apoptosis. In PCLS derived from bile duct ligated animals, both alpha-SM actin and PDGF receptor-beta expression decreased after 48 h in culture with a massive apoptosis. In PCLS derived from human fibrotic livers, alpha-SM actin expression was dramatically reduced after 48 h in culture. CONCLUSIONS: After CCl4 treatment, a proportion of myofibroblasts derived from hepatic stellate cells seems to dedifferentiate while in bile duct ligation model, myofibroblasts derived from portal fibroblasts disappear by apoptosis, underlining the relevance of this model to evaluate the mechanisms involved in fibrotic liver remodelling.

Actins↗

PubMed2000

The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling.

The determination of animal form depends on the coordination of events that lead to the morphological patterning of cells. This epigenetic view of development suggests that embryonic structures arise as a consequence of environmental influences acting on the properties of cells, rather than an unfolding of a completely genetically specified and preexisting invisible pattern. Specialized cells of developing multicellular organisms are surrounded by a complex extracellular matrix (ECM), comprised largely of different collagens, proteoglycans, and glycoproteins. This ECM is a substrate for tissue morphogenesis, lends support and flexibility to mature tissues, and acts as an epigenetic informational entity in the sense that it transduces and integrates intracellular signals via distinct cell surface receptors. Consequently, ECM-receptor interactions have a profound influence on major cellular programs including growth, differentiation, migration, and survival. In contrast to many other ECM proteins, the tenascin (TN) family of glycoproteins (TN-C, TN-R, TN-W, TN-X, and TN-Y) display highly restricted and dynamic patterns of expression in the embryo, particularly during neural development, skeletogenesis, and vasculogenesis. These molecules are reexpressed in the adult during normal processes such as wound healing, nerve regeneration, and tissue involution, and in pathological states including vascular disease, tumorigenesis, and metastasis. In concert with a multitude of associated ECM proteins and cell surface receptors that include members of the integrin family, TN proteins impart contrary cellular functions, depending on their mode of presentation (i.e., soluble or substrate-bound) and the cell types and differentiation states of the target tissues. Expression of tenascins is regulated by a variety of growth factors, cytokines, vasoactive peptides, ECM proteins, and biomechanical factors. The signals generated by these factors converge on particular combinations of cis-regulatory elements within the recently identified TN gene promoters via specific transcriptional activators or repressors. Additional complexity in regulating TN gene expression is achieved through alternative splicing, resulting in variants of TN polypeptides that exhibit different combinations of functional protein domains. In this review, we discuss some of the recent advances in TN biology that provide insights into the complex way in which the ECM is regulated and how it functions to regulate tissue morphogenesis and gene expression.

Adult↗

PubMed1988

Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling.

Proteins undergo a series of nonenzymatic reactions with glucose over time to form advanced glycosylation end products (AGEs). Macrophages have a receptor that recognizes the AGE moiety and mediates the uptake and degradation of AGE proteins. This removal process is associated with the production and secretion of cachectin (tumor necrosis factor) and interleukin-1, two cytokines with diverse and seemingly paradoxical biological activities. The localized release and action of these cytokines could account for the coordinated removal and replacement of senescent extracellular matrix components in normal tissue homeostasis.

Glycosylation↗

PubMed1995

Detection of c-fms protooncogene in early mouse embryos by whole mount in situ hybridization indicates roles for macrophages in tissue remodelling.

The c-fms protoncogene which encodes the receptor for macrophage colony-stimulating factor (CSF-1) was localized in the developing mouse embryo by whole in situ hybridization. c-fms was expressed first in placental trophoblasts. Around 9.5 dpc, isolated c-fms-positive cells became detectable in the yolk sac and by 10.5 dpc large numbers were detectable throughout the embryo. The localization of c-fms expression was consistent with its restriction to macrophages, and with the location of those macrophages in sites of tissue turnover and extensive cell death.

Animals↗

PubMed2004

Collagen fibers an important entity in skin tissues remodeling.

Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) evaluation were carried out in the in vivo skin construct using fibrin as biomaterial. To investigate its progressive remodeling, nude mice were grafted and the Extracellular Matrix (ECM) components were studied at four and eight weeks post-grafting. It was discovered that by 4 weeks of remodeling the skin construct acquired its native structure.

Animals↗

PubMed1991

The extended subperiosteal face lift: a definitive soft-tissue remodeling for facial rejuvenation.

The subperiosteal face lift described by Psillakis has been criticized for not showing a more dramatic improvement over conventional brow/face lift procedures. His approach also has a significantly high incidence of nerve injury. This study reports our anatomic findings and surgical modifications, which have permitted a significant improvement in the safety of execution and clinical results using the subperiosteal face lift concept. Pertinent points of applied local anatomy and dissection techniques are as follows: First, we use extensive interconnected subperiosteal dissection that includes the entire zygomatic arch. This allows better repositioning of the deep soft tissues of the entire upper face, most of the midface, and indirectly, key structures of the lower face. Second, the upward pull of the muscles of the cheek and mouth will produce an elevation of the corner of the mouth, affecting positively the smiling mechanism, the oral frowning, and the jowls. Third, the dissection deep to both layers of the temporal fascia decreases the risk of injury to the frontalis nerve. Fourth, the temporal fascia is used as a lifter and anchoring element of the entire cheek-perioral soft tissues as opposed to the periorbital fibrofatty tissues. This will decrease the risk of injuring the frontal and zygomatic branches of the facial nerve. These modifications have been used in 28 patients. Our rate of patient satisfaction has been high, and no complications with regard to nerve injury have been observed. This compares favorably with our initial 60 patients, in whom the Psillakis or Tessier approach was used. In these patients, there was an 11 and 20 percent rate of nerve injury, respectively.

Aged↗

PubMed2002

Tissue remodeling following submassive hemorrhagic necrosis in rat livers induced by an intraperitoneal injection of dimethylnitrosamine.

We examined regeneration and fibrosis in the necrotic areas of hepatic stellate cells (HSCs). Acute hepatic injury was induced in rats by administration of an intraperitoneal injection of high-dose dimethylnitrosamine (50 mg/kg body weight). Liver samples were obtained from rats 6, 12, 24, 36 h and 2, 3, 5, 7, 10, and 14 days after the injection. They were examined by light and electron microscopy and by immunohistochemical methods. Hemorrhagic necrosis became most prominent 36 h after treatment and extended into zones 3 and 2. In the submassive necrotic areas the sinusoidal structure was destroyed. No HSCs positive for alpha-smooth muscle actin or desmin were present. On day 5, when necrotic tissues were almost removed by infiltrating macrophages, HSCs strongly positive for alpha-smooth muscle actin and desmin appeared along the surface of the preserved parenchyma and migrated into the necrotic areas along the residual reticulin fibers. By day 14 most of the necrotic areas were almost completely replaced by the regeneration of hepatocytes and central to central (C-C) bridging fibrosis. Our results indicate that following submassive complete necrosis, HSCs in the preserved liver parenchyma have roles in the formation of sinusoidal wall for remodeling in necrotic areas via their activation, proliferation, and migration into the necrotic areas.

Actins↗

PubMed1998

Tissue remodelling in the adrenal gland.

Adaptation of the adrenal gland to the demands of the organism is regulated functionally and structurally. Three common hypotheses on zonation in the adrenal gland, the migrational, zonal, and transformation field theories, try independently to reconcile the findings on structure, proliferation, and cell death. The classical theories on zonation are revisited in the light of recent data on cell death and renewal. In accordance with data on cell death as immunoreactivity against FAS(CD 95), an apoptosis-inducing receptor, in situ end labelling of fragmented DNA, and ultrastructural analyses, programmed cell death (PCD) occurs throughout the whole organ. The angiotensin II receptor subtypes described in the adrenal allow an additional regulation of tissue homeostasis by proliferative and even by the antiproliferative effects of the angiotensin II type 2 receptor. Proto-oncogenes are involved in the regulation of cell cycle and PCD, and adrenocorticotropin asserts its tissue integrating and differentiating effects by regulating proto-oncogenes such as c-jun, c-fos, jun-B and c-myc. Polypeptides involved in proliferation and DNA repair, such as proliferating cell nuclear antigen and Ki-67, have been found within zones of expected cell senescence. The expression of the class II major histocompatibility complex on normal adrenocortical cells allows cell-to-cell communication with the immune system and may trigger the Fas/Fas-ligand system to permit tissue regression and decreasing activity in both systems. In summary, new data allow us to reappraise and to reconcile the classical theories. Apoptosis is a physiological process in the adrenal gland. There is a differential regulation of apoptosis in the different zones. An investigation of this process may elucidate the basic mechanisms of adrenal zonation.

Adrenal Glands↗

PubMed2006

Tissue remodeling during maturation of the Drosophila wing.

The final step in morphogenesis of the adult fly is wing maturation, a process not well understood at the cellular level due to the impermeable and refractive nature of cuticle synthesized some 30 h prior to eclosion from the pupal case. Advances in GFP technology now make it possible to visualize cells using fluorescence after cuticle synthesis is complete. We find that, between eclosion and wing expansion, the epithelia within the folded wing begin to delaminate from the cuticle and that delamination is complete when the wing has fully expanded. After expansion, epithelial cells lose contact with each other, adherens junctions are disrupted, and nuclei become pycnotic. The cells then change shape, elongate, and migrate from the wing into the thorax. During wing maturation, the Timp gene product, tissue inhibitor of metalloproteinases, and probably other components of an extracellular matrix are expressed that bond the dorsal and ventral cuticular surfaces of the wing following migration of the cells. These steps are dissected using the batone and Timp genes and ectopic expression of alphaPS integrin, inhibitors of Armadillo/beta-catenin nuclear activity and baculovirus caspase inhibitor p35. We conclude that an epithelial-mesenchymal transition is responsible for epithelial delamination and dissolution.

Animals↗

PubMed1994

Apoptosis during macrophage-dependent ocular tissue remodelling.

We have characterized the nature and pattern of cell death during regression of the pupillary membrane, a developmentally transient capillary network found in the anterior chamber of the eye. This analysis has revealed that the cellular components of the pupillary membrane include vascular endothelial cells in an intricate network of fine capillaries as well as attendant macrophages. The capillaries are situated on the anterior surface of the lens and held in relative position by a cobweb-like meshwork of extracellular matrix fibres that regress along with the cellular components of this structure. Cell death during regression of the pupillary membrane is characteristic of apoptosis. Specifically, apoptotic bodies containing condensed chromatin can be observed in vascular endothelial cells and genomic DNA isolated from the pupillary membrane shows the nucleosomal fragmentation pattern typical of apoptotic cells. Using a method for labelling fragmented DNA in tissue preparations (TUNEL), we have assessed the overall pattern of apoptotic cell death during pupillary membrane regression. We find that apoptosis occurs either in single cells in healthy vessels or synchronously along the entire length of a capillary segment. Both morphological and TUNEL analysis indicate that capillary regression occurs from junction to junction one segment at a time. We propose a model to explain the pattern of capillary regression observed and conclude from these and previous experiments (Lang and Bishop (1993) Cell 74, 453-462), that during regression of the pupillary membrane, the macrophage elicits target cell death by inducing apoptosis.

Animals↗

PubMed2006

Prolonged treatment with the beta3-adrenergic agonist CL 316243 induces adipose tissue remodeling in rat but not in guinea pig: 1) fat store depletion and desensitization of beta-adrenergic responses.

Beta3-adrenergic agonists have been considered as potent antiobesity and antidiabetic agents mainly on the basis of their beneficial actions discovered twenty years ago in obese and diabetic rodents. The aim of this work was to verify whether prolonged treatment with a beta3-adrenergic agonist known to stimulate lipid mobilisation, could promote desensitization of beta-adrenergic responses. Wistar rats and guinea pigs were treated during one week with CL 316243 (CL, 1 mg/kg/d) by implanted osmotic minipumps. In control animals, beta3-adrenergic agonists were lipolytic in rat but not in guinea pig adipocytes. CL-treatment did not alter body weight gain in both species, but reduced fat stores in rats. Lipolysis stimulation by forskolin was unmodified but responses to beta1-, beta2- and beta3-agonists were reduced in visceral or subcutaneous white adipose tissues of CL-treated rats. Similarly, the beta3-adrenergic-dependent impairment of insulin action on glucose transport and lipogenesis in rat adipocytes was diminished after CL-treatment. In rat adipocytes, [125I]ICYP binding and beta3-adrenoceptor mRNA levels were reduced after sustained CL administration. These findings show that CL 316243 exerts (beta3-adrenergic lipolytic and antilipogenic effects in rat adipocytes. These actions, which are likely involved in the fat depletion observed in rat, also lead to the desensitization of all beta-adrenergic responses. Therefore this desensitization, together with the lack of slimming action in guinea pig, seriously attenuates the usefulness of beta3-agonists as antiobesity agents, and may explain why such agonists have not been conducted to a widespread clinical use.

Adipocytes, White↗

PubMed2001

Thyroid hormone regulation of apoptotic tissue remodeling during anuran metamorphosis.

Anuran metamorphosis involves systematic transformations of individual organs in a thyroid hormone (TH)-dependent manner. Morphological and cellular studies have shown that the removal of larval organs/tissues such the tail and the tadpole intestinal epithelium is through programmed cell death or apoptosis. Recent molecular investigations suggest that TH regulates metamorphosis by regulating target gene expression through thyroid hormone receptors (TRs), which are DNA-binding transcription factors. Cloning and characterization of TH response genes show that diverse groups of early response genes are induced by TH. The products of these TH response genes are believed to directly or indirectly affect the expression and/or functions of cell death genes, which are conserved at both sequence and function levels in different animal species. A major challenge for future research lies at determining the signaling pathways leading to the activation of apoptotic processes and whether different death genes are involved in the regulation of apoptosis in different tissues/organs to effect tissue-specific transformations.

Animals↗

PubMed2006

Oral administration of diferuloylmethane (curcumin) suppresses proinflammatory cytokines and destructive connective tissue remodeling in experimental abdominal aortic aneurysms.

Chronic transmural inflammation and proteolytic destruction of medial elastin are key mechanisms in the development of abdominal aortic aneurysms (AAAs). Diferuloylmethane (curcumin) is a major component of the food additive tumeric, which has been shown to have anti-inflammatory properties. To determine if ingestion of curcumin influences aneurysmal degeneration, C57Bl/6 mice underwent transient elastase perfusion of the abdominal aorta to induce the development of AAAs, followed by daily oral gavage with 100 mg/kg curcumin (n = 36) or water alone (n = 31). By 14 days, mice in the control group developed a mean increase in aortic diameter of 162.8 +/- 4.6% along with a dense mononuclear inflammation and destruction of medial elastin. By comparison, the mean increase in aortic diameter in the curcumin-treated group was only 133.2 +/- 5.2% (p < 0.0001). Although aortic wall inflammation was similar between the groups, the structural integrity of medial elastin was significantly greater in curcumin-treated mice. Curcumin-treated mice also exhibited relative decreases in aortic tissue activator protein-1 and nuclear factor kappaB DNA binding activities and significantly lower aortic tissue concentrations of interleukin-1beta (IL-1beta), IL-6, monocyte chemoattractant protein-1, and matrix metalloproteinase-9 (all p < 0.05). These data demonstrate for the first time that oral administration of curcumin can suppress the development of experimental AAAs, along with structural preservation of medial elastin fibers and reduced aortic wall expression of several cytokines, chemokines, and proteinases known to mediate aneurysmal degeneration. The possibility that dietary ingestion of curcumin may have a beneficial effect in degenerative aortic aneurysms warrants further consideration.

Administration, Oral↗

PubMed2006

Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling?

Genetic studies in familial pulmonary arterial hypertension (FPAH) have revealed heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR-II), a receptor for the transforming growth factor (TGF)-beta/bone morphogenetic protein (BMP) superfamily. PAH is characterized by intense remodeling of small pulmonary arteries by myofibroblast and smooth muscle proliferation. BMPR-II mutation in pulmonary artery smooth muscle cells contributes to abnormal growth responses to BMPs and TGF-beta. Reduced expression or function of BMPR-II signaling leads to exaggerated TGF-beta signaling and altered cellular responses to TGF-beta. The likely mechanism involves an interaction between BMP and TGF-beta-regulated Smad pathways. In endothelial cells, BMPR-II mutation increases the susceptibility of cells to apoptosis. The combination of increased endothelial apoptosis and failure of growth suppression in pulmonary artery smooth muscle cells provides important clues to the cellular pathogenesis of PAH. The reciprocal regulation of TGF-beta and BMP signaling in models of tissue repair may provide new approaches to our understanding of lung disease.

Animals↗

PubMed2001

Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1.

This study examines endothelin-induced modulation of extracellular matrix synthesis and remodeling by fibroblasts, and its potential role in the pathogenesis of systemic sclerosis (scleroderma). Endothelin-1 promoted fibroblast synthesis of collagen types I and III, but not fibronectin, by a mechanism dependent upon both ETA and ETB receptors. Conversely, endothelin-1 inhibited both protein expression of matrix metalloproteinase 1 and zymographic activity exclusively via ETA receptors. A dual regulatory role for endothelin-1 in transcriptional regulation was suggested by the ability of endothelin-1 to enhance steady-state levels of collagen mRNA and activate the proalpha2(I) collagen (Col1a2) promoter, but in contrast to reduce matrix metalloproteinase 1 transcript expression and suppress transcription of a human matrix metalloproteinase 1 promoter reporter construct in transient transfection assays. Although endothelin-1 significantly enhanced remodeling of three-dimensional collagen lattices populated by normal fibroblasts, this was not observed for lattices populated by systemic sclerosis fibroblasts. Promotion of matrix remodeling was dependent upon ETA receptor expression and was blocked by specific inhibitors of tyrosine kinases or protein kinase C. Reverse transcriptase polymerase chain reaction, S1 nuclease, and functional cell surface binding studies showed that normal and systemic sclerosis fibroblasts express both ETA and ETB receptors (predominantly ETA), but that ETA receptor mRNA levels and ETA binding sites on fibroblasts cultured from systemic sclerosis skin biopsies are reduced by almost 50%. Endothelin-1 is thus able to induce a fibrogenic phenotype in normal fibroblasts that is similar to that of lesional systemic sclerosis fibroblasts. Moreover, reduced responsiveness to exogenous endothelin-1 in systemic sclerosis suggests that downstream pathways may have already been activated in vivo. These data further implicate dysregulated endothelin-receptor pathways in fibroblasts in the pathogenesis of connective tissue fibrosis.

Cells, Cultured↗