Reversal Of Fibrosis Research Articles

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): A systematic review.

There are no licensed drugs for nonalcoholic fatty liver disease (NAFLD), and there is a lack of consensus on the best outcome measures for controlled trials. This systematic review aimed to evaluate the efficacy of GLP‐1 RAs in the management of NAFLD, the degree of heterogeneity in trial design and the robustness of conclusions drawn from these clinical trials. We searched publication databases and clinical trial registries through 2 November 2019 for clinical trials with NAFLD. We evaluated improvements in histological findings, noninvasive markers of hepatic steatosis, inflammation, and fibrosis, insulin resistance and anthropometric measures. Our final analysis included 24 clinical trials, comprising 6313 participants with a mean duration of 37 weeks. Four clinical trials, including RCT (n = 1), single‐arm studies (n = 2) and case series studies (n = 1), used biopsy‐confirmed liver histological change as their end‐points. The remaining studies (n = 20) used surrogate end‐points. GLP‐1 RAs were effective for the improvement in hepatic inflammation, hepatic steatosis and fibrosis. More importantly, GLP‐1 RAs showed promise in improving the histological features of NASH. In addition, 8 ongoing trials were identified. In this systematic review of published and ongoing clinical trials of the efficacy of GLP‐1RAs for NAFLD, we found that GLP‐1 RAs are effective for hepatic steatosis and inflammation, with the potential to reverse fibrosis. Further prospective studies of sufficient duration using histological end‐points are needed to fully assess the efficacy of GLP‐1 RAs in the management of NAFLD.

Bioactive Components and Hepatoprotective Activity of Acanthopleura vaillantii (Chiton) against Carbon Tetrachloride-Induced Hepatotoxicity in Mice

Marine animals provide a wide range of bioactive compounds that may offer new and innovative therapeutic tools for use in various diseases. In this study, the bioactive compounds in the extracts of Acanthopleura vaillantii (chiton) were identified, their antioxidant property assayed and the hepatoprotective activity evaluated in a carbon tetrachloride-induced hepatotoxicity model in mice. The gas chromatography-mass spectrometry (GC-MS) analysis identified mostly the polyphenolic compounds. The antioxidant assay showed that the chiton extract had radical scavenging activity. Intraperitoneal injection of the chiton extract in mice increased the hepatic enzymes and albumin content at the dose level of 10 mg chiton /kg of body weight. While administration of 20 mg chiton extract in mice was with the normalized serum albumin (Alb), alanine aminotransferases (ALT) and aspartate (AST). The histological examination of the liver sections from the 10 and 20 mg chitons treated groups showed substantial attenuation of the degenerative cellular changes, recovery from necrosis and reversal of liver fibrosis induced by the carbon tetrachloride intoxication.

SO041THE EFFECT AND MECAHNISM OF THE LOX IN AT1R/Β-ARRESTIN BIASED PATHWAY INDUCED RENAL INTERSTITIAL FIBROSIS

Abstract Background and Aims We studied the downstream and mechanism of β-arrestins signaling in renal fibrosis process and the role of lysyl oxidase (LOX) in the AT1R-β-arrestins pathway. Method The mechanism of β-arrestins signaling was studied in normal rat kidney tubule epithelial cells (NRK-52E) treated with SII in vitro. BAPN or placebo was administered during ischemia reperfusion (IR)-induced fibrosis progression. Collagen crosslinking and fibrosis progression were assessed histologically and biochemically. Results The mRNA and protein levels of β-arrestin-1 and β-arrestin-2 were significantly upregulated in renal fibrosis model both in vitro and in vivo. SII activated the ERK-STAT3 PY705 but not STAT3-Try727 in nucleus of NRK-52E cells, which effects were abolished when transfection of siRNA targeting β-arrestin-1 and β-arrestin-2 or pretreated with PD98059 (MEK inhibitor). LOX was strongly induced in fibrotic kidney and NRK-52E cells treated with SII. Active LOX significantly increased collagen crosslinking. In established IR-28d renal fibrosis, LOX inhibition promoted fibrosis reversal and with a 25% decrease insoluble collagen. Gene silencing of β-arrestin-1 + 2 or STAT3 apparently inhibited SII-induced LOX expression in vitro. Besides, chromatin immunoprecipitation (ChIP) assay clearly demonstrating the interaction between STAT3 and the LOX promoter, which indicated LOX is a direct target gene of SII-β-arrestins-STAT3 signaling. Conclusion The ERK/STAT3 was downstream of AT1R-β-arrestins, ERK entered the nucleus and activated STAT3-PY705. LOX mediates collagen crosslinking and fibrotic matrix stabilization during renal fibrosis via the AT1R-β-arrestins-ERK-STAT3-PY705 signaling. By blocking this profibrotic pathway, therapeutic LOX inhibition attenuates the fibrosis and suggesting target the LOX has significant potency for the treatment of patients with fibrotic kidney disorders.

CD10/Neprilysin Enrichment in Infrapatellar Fat Pad–Derived Mesenchymal Stem Cells Under Regulatory-Compliant Conditions: Implications for Efficient Synovitis and Fat Pad Fibrosis Reversal

Background: Synovitis and infrapatellar fat pad (IFP) fibrosis participate in various conditions of the knee. Substance P (SP), a neurotransmitter secreted within those structures and historically associated with nociception, also modulates local neurogenic inflammatory and fibrotic responses. Exposure of IFP mesenchymal stem cells (IFP-MSCs) to a proinflammatory/profibrotic environment (ex vivo priming with TNFα, IFNγ, and CTGF) induces their expression of CD10/neprilysin, effectively degrading SP in vitro and in vivo. Purpose/Hypothesis: The purpose was to test the therapeutic effects of IFP-MSCs processed under regulatory-compliant protocols, comparing them side-by-side with standard fetal bovine serum (FBS)–grown cells. The hypothesis was that when processed under such protocols, IFP-MSCs do not require ex vivo priming to acquire a CD10-rich phenotype efficiently degrading SP and reversing synovitis and IFP fibrosis. Study Design: Controlled laboratory study. Methods: Human IFP-MSCs were processed in FBS or either of 2 alternative conditions—regulatory-compliant pooled human platelet lysate (hPL) and chemically reinforced medium (Ch-R)—and then subjected to proinflammatory/profibrotic priming with TNFα, IFNγ, and CTGF. Cells were assessed for in vitro proliferation, stemness, immunophenotype, differentiation potential, transcriptional and secretory profiles, and SP degradation. Based on a rat model of acute synovitis and IFP fibrosis, the in vivo efficacy of cells degrading SP plus reversing structural signs of inflammation and fibrosis was assessed. Results: When compared with FBS, IFP-MSCs processed with either hPL or Ch-R exhibited a CD10High phenotype and showed enhanced proliferation, differentiation, and immunomodulatory transcriptional and secretory profiles (amplified by priming). Both methods recapitulated and augmented the secretion of growth factors seen with FBS plus priming, with some differences between them. Functionally, in vitro SP degradation was more efficient in hPL and Ch-R, confirmed upon intra-articular injection in vivo where CD10-rich IFP-MSCs also dramatically reversed signs of synovitis and IFP fibrosis even without priming or at significantly lower cell doses. Conclusion: hPL and Ch-R formulations can effectively replace FBS plus priming to induce specific therapeutic attributes in IFP-MSCs. The resulting fine-tuned, regulatory-compliant, cell-based product has potential future utilization as a novel minimally invasive cell therapy for the treatment of synovitis and IFP fibrosis. Clinical Relevance: The therapeutic enhancement of IFP-MSCs manufactured under regulatory-compliant conditions suggests that such a strategy could accelerate the time from preclinical to clinical phases. The therapeutic efficacy obtained at lower MSC numbers than currently needed and the avoidance of cell priming for efficient results could have a significant effect on the design of clinical protocols to potentially treat conditions involving synovitis and IFP fibrosis.

Impaired Myofibroblast Dedifferentiation Contributes to Nonresolving Fibrosis in Aging.

Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease with no cure. Although IPF is widely regarded as a disease of aging, the cellular mechanisms that contribute to this age-associated predilection remain elusive. In this study, we sought to evaluate the consequences of senescence on myofibroblast cell fate and fibrotic responses to lung injury in the context of aging. We demonstrated that nonsenescent lung myofibroblasts maintained the capacity for dedifferentiation, whereas senescent/IPF myofibroblasts exhibited an impaired capacity for dedifferentiation. We previously demonstrated that the transcription factor MyoD acts as a critical switch in the differentiation and dedifferentiation of myofibroblasts. Here, we demonstrate that decreased levels of MyoD preceded myofibroblast dedifferentiation and apoptosis susceptibility in nonsenescent cells, whereas MyoD expression remained elevated in senescent/IPF myofibroblasts, which failed to undergo dedifferentiation and demonstrated resistance to apoptosis. Genetic strategies to silence MyoD restored the susceptibility of IPF myofibroblasts to undergo apoptosis and led to a partial reversal of age-associated persistent fibrosis in vivo. The capacity for myofibroblast dedifferentiation and subsequent apoptosis may be critical for normal physiologic responses to tissue injury, whereas restricted dedifferentiation and apoptosis resistance in senescent cells may underlie the progressive nature of age-associated human fibrotic disorders. These studies support the concept that senescence may promote profibrotic effects via impaired myofibroblast dedifferentiation and apoptosis resistance, which contributes to myofibroblast accumulation and ultimately persistent fibrosis in aging.

Targeting Hepatic Stellate Cells for the Treatment of Liver Fibrosis by Natural Products: Is It the Dawning of a New Era?

Liver fibrosis is a progressive liver damage condition that is worth studying widely. It is important to target and alleviate the disease at an early stage before turning into later cirrhosis or liver cancer. There are currently no direct medicines targeting the attenuation or reversal of liver fibrosis, and so there is an urgent need to look into this area. Traditional Chinese Medicine has a long history in using herbal medicines to treat liver diseases including fibrosis. It is time to integrate the ancient wisdom with modern science and technology to look for the best solution to the disease. In this review, the principal concept of the pathology of liver fibrosis will be described, and then some of the single compounds isolated from herbal medicines, including salvianolic acids, oxymatrine, curcumin, tetrandrine, etc. will be discussed from their effects to the molecular mechanism behind. Molecular targets of the compounds are analyzed by network pharmacology approach, and TGFβ/SMAD was identified as the most common pathway. This review serves to summarize the current findings of herbal medicines combining with modern medicines in the area of fibrosis. It hopefully provides insights in further pharmaceutical research directions.

Compromised DNA repair is responsible for diabetes‐associated fibrosis

Diabetes‐associated organ fibrosis, marked by elevated cellular senescence, is a growing health concern. Intriguingly, the mechanism underlying this association remained unknown. Moreover, insulin alone can neither reverse organ fibrosis nor the associated secretory phenotype, favoring the exciting notion that thus far unknown mechanisms must be operative. Here, we show that experimental type 1 and type 2 diabetes impairs DNA repair, leading to senescence, inflammatory phenotypes, and ultimately fibrosis. Carbohydrates were found to trigger this cascade by decreasing the NAD+/NADH ratio and NHEJ‐repair in vitro and in diabetes mouse models. Restoring DNA repair by nuclear over‐expression of phosphomimetic RAGE reduces DNA damage, inflammation, and fibrosis, thereby restoring organ function. Our study provides a novel conceptual framework for understanding diabetic fibrosis on the basis of persistent DNA damage signaling and points to unprecedented approaches to restore DNA repair capacity for resolution of fibrosis in patients with diabetes.

From the Editor’s Desk…

From the Editor’s Desk…

The Vascular Involvement in Soft Tissue Fibrosis-Lessons Learned from Pathological Scarring.

Soft tissue fibrosis in important organs such as the heart, liver, lung, and kidney is a serious pathological process that is characterized by excessive connective tissue deposition. It is the result of chronic but progressive accumulation of fibroblasts and their production of extracellular matrix components such as collagens. Research on pathological scars, namely, hypertrophic scars and keloids, may provide important clues about the mechanisms that drive soft tissue fibrosis, in particular the vascular involvement. This is because these dermal fibrotic lesions bear all of the fibrotic characteristics seen in soft tissue fibrosis. Moreover, their location on the skin surface means they are readily observable and directly treatable and therefore more accessible to research. We will focus here on the roles that blood vessel-associated cells play in cutaneous scar pathology and assess from the literature whether these cells also contribute to other soft tissue fibroses. These cells include endothelial cells, which not only exhibit aberrant functions but also differentiate into mesenchymal cells in pathological scars. They also include pericytes, hepatic stellate cells, fibrocytes, and myofibroblasts. This article will review with broad strokes the roles that these cells play in the pathophysiology of different soft tissue fibroses. We hope that this brief but wide-ranging overview of the vascular involvement in fibrosis pathophysiology will aid research into the mechanisms underlying fibrosis and that this will eventually lead to the development of interventions that can prevent, reduce, or even reverse fibrosis formation and/or progression.

Amniotic fluid mesenchymal stem cells ameliorate lung alveolar epithelium regeneration and reverse lung fibrosis of chronic obstructive pulmonary disease

Pulmonary emphysema progression is attributed not only to alveolar structure loss and pulmonary regeneration impairment but also to excessive inflammatory response, proteolytic and anti‐proteolytic activity imbalance, lung epithelial cell apoptosis and abnormal lung remodeling. To ameliorate lung damage with higher efficiency through lung tissue engineering and cell therapy, predifferentiating graft cells into more restricted cell types before transplantation could enhance their ability to anatomically and functionally integrate into damaged lung. An optimal lung epithelial progenitor‐like cells (LEPLCs) predifferentiation condition has been established in eGFP‐expressing amniotic fluid mesenchymal stem cells (AFMSCs). Transplantation of LEPLCs significantly improved regeneration of lung tissue as they integrated into the lung alveolar structure, relieved airway inflammation, alleviated amount of DNA damage in alveolar cells, increased expression of growth factors such as vascular endothelial growth factor, and reduced expression of matrix metalloproteinases and lung remodeling factors when compared with the elastase‐induced pulmonary emphysema mice injected with AFMSCs. In conclusion, transplantation of predifferentiated AFMSCs through intratracheal injection showed better alveolar regeneration and reverse lung fibrosis in PPE‐induced pulmonary emphysema mice.Support or Funding InformationThis research was supported by grant MOE‐108‐S‐0023‐A from the Ministry of Education of Taiwan.

Possible Reversal of Carbon Tetra Chloride-induced Liver Fibrosis in Sprague Dawley Rats treated with Stromal Vascular Fraction and Activated Platelet Rich Plasma

Background: Stromal vascular fraction (SVF) is considered a promising source of stem cells, but potential of treatment of damaged liver has not been fully explored. Aim: In this present study, we sought to evaluate the hepato-regenerative effect of SVF combined with activated platelet rich plasma (aPRP) on carbon tetrachloride (CCl4) induced hepatic injury in Sprague Dawley (SD) rats. Material and Methods: Liver fibrosis was induced using CCl4 in 30 SD rats. Sixteen rats survived and were divided into two groups – control and treated. SVF and aPRP were prepared by standard methods from three normal donor rats. Combination SVF-aPRP was administered intravenously via the lateral tail vein in treated group animals, on Day 0, 7 and 14. Normal saline of same dose volume was administered to the control group. AST and ALT levels were monitored throughout the study duration of 28 days. Gross and histopathological analysis of liver was performed post sacrifice on Day 28. Results: Decrease in the ALT/AST levels over the duration of study was observed in both control and treated groups, with a statistically significant reduction in AST/ALT levels between Control ad Treated groups on Day 28. Gross morphological evaluation, fibrosis and cirrhosis grades also showed reduction between control and treated groups. Conclusion: Observations of enzyme levels, gross and histopathological analyses revealed a reduction in severity of liver fibrosis in the treated group. However, we have identified additional parameters that need to be evaluated to corroborate these research findings.

Non-ischemic dilated cardiomyopathy and cardiac fibrosis.

Cardiac fibrosis is associated with non-ischemic dilated cardiomyopathy, increasing its morbidity and mortality. Cardiac fibroblast is the keystone of fibrogenesis, being activated by numerouscellular and humoral factors. Macrophages, CD4+ and CD8+T cells, mast cells, and endothelial cells stimulate fibrogenesis directly by activating cardiac fibroblasts and indirectly by synthetizing various profibrotic molecules. The synthesis of type 1 and type 3 collagen, fibronectin, and α-smooth muscle actin is rendered by various mechanisms like transforming growth factor-beta/small mothers against decapentaplegic pathway, renin angiotensin system, and estrogens, which in turn alter the extracellular matrix. Investigating the underlying mechanisms will allow the development of diagnostic and prognostic tools and discover novel specific therapies. Serum biomarkers aid in the diagnosis and tracking of cardiac fibrosis progression. The diagnostic gold standard is cardiac magnetic resonance with gadolinium administration that allows quantification of cardiac fibrosis either by late gadolinium enhancement assessment or by T1 mapping. Therefore, the goal is to stop and even reverse cardiac fibrosis by developing specific therapies that directly target fibrogenesis, in addition to the drugs used to treat heart failure. Cardiac resynchronization therapy had shown to revert myocardial remodeling and to reduce cardiac fibrosis. The purpose of this review is to provide an overview of currently available data.

A Deactivation Factor of Fibrogenic Hepatic Stellate Cells Induces Regression of Liver Fibrosis in Mice

Hepatic stellate cells (HSCs), a key player in the progression of liver fibrosis, are activated by various inflammatory stimuli and converted to myofibroblast-like cells with excessive collagen production. Despite many attempts to suppress activation of HSCs or inhibit collagen production in activated HSCs, their clinical applications have not been established yet. Recently, the deactivation of HSCs has been reported as a mechanism underlying the reversibility of experimental liver fibrosis. In the present study, we sought for deactivation factors of HSCs that induce regression of established liver fibrosis. We identified transcription factor 21 (Tcf21) as one of the transcription factors whose expression was up-regulated in parallel to the differentiation of fetal HSCs. Expression of Tcf21 in HSCs remarkably decreased during culture-induced activation in vitro and in murine and human fibrotic liver tissue in vivo. This reduced Tcf21 expression was recovered during the spontaneous regression of murine liver fibrosis. Tcf21 was also examined for its effects by adeno-associated virus serotype 6-mediated Tcf21 gene transfer into cultured activated HSCs and mice with carbon tetrachloride- or methionine-choline deficient diet-induced liver fibrosis. Overexpression of Tcf21 in activated HSCs not only suppressed fibrogenic gene expression but also restored cells, at least in part, to a quiescent phenotype both in vitro and in vivo. These phenotypic changes of HSCs were accompanied by the regression of steatohepatitis and fibrosis and improved hepatic architecture and function. Tcf21 has been identified as a deactivation factor of fibrogenic HSCs, providing insight into a treatment strategy for the otherwise intractable liver fibrosis.

Cardiac Fibroblast Diversity.

Cardiac fibrosis is a pathological condition that occurs after injury and during aging. Currently, there are limited means to effectively reduce or reverse fibrosis. Key to identifying methods for curbing excess deposition of extracellular matrix is a better understanding of the cardiac fibroblast, the cell responsible for collagen production. In recent years, the diversity and functions of these enigmatic cells have been gradually revealed. In this review, I outline current approaches for identifying and classifying cardiac fibroblasts. An emphasis is placed on new insights into the heterogeneity of these cells as determined by lineage tracing and single-cell sequencing in development, adult, and disease states. These recent advances in our understanding of the fibroblast provide a platform for future development of novel therapeutics to combat cardiac fibrosis.

Honokiol: A polyphenol neolignan ameliorates pulmonary fibrosis by inhibiting TGF-β/Smad signaling, matrix proteins and IL-6/CD44/STAT3 axis both in vitro and in vivo

Pulmonary fibrosis (PF) is an epithelial/fibroblastic crosstalk disorder of the lungs with highly complex etiopathogenesis. Limited treatment possibilities are responsible for poor prognosis and mean survival rate of 3 to 5 years of PF patients after definite diagnosis. Once thought to be an irreversible disorder, recent evidences have brought into existence the concept of organ fibrosis reversibility due to plastic nature of fibrotic tissues. These findings have kindled interest among the scientific community and given a new direction for research in the arena of fibrosis for developing new anti-fibrotic therapies. The current study is designed to evaluate the anti-fibrotic effects of Honokiol (HNK), a neolignan active constituent from Magnolia officinalis. This study has been conducted in TGF-β1 induced in vitro model and 21 day in vivo murine model of Bleomycin induced PF. The findings of our study suggest that HNK was able to inhibit fundamental pathways of epithelial to mesenchymal transition (EMT) and TGF-β/Smad signaling both in vitro and in vivo. Additionally, HNK also attenuated collagen deposition and inflammation associated with fibrosis. We also hypothesized that HNK interfered with IL-6/CD44/STAT3 axis. As hypothesized, HNK significantly mitigated IL-6/CD44/STAT3 axis both in vitro and in vivo as evident from outcomes of various protein expression studies like western blotting, immunohistochemistry and ELISA. Taken together, it can be concluded that HNK reversed pulmonary fibrotic changes in both in vitro and in vivo experimental models of PF and exerted anti-fibrotic effects majorly by attenuating EMT, TGF-β/Smad signaling and partly by inhibiting IL-6/CD44/STAT3 signaling axis.

Curcumol may reverse early and advanced liver fibrogenesis through downregulating the uPA/uPAR pathway.

Previous studies have suggested strong antifibrotic activity of curcumol in the liver; the underlying mechanisms of which, however, remain largely unknown. Aiming to investigate the role of curcumol in regulating early and advanced liver fibrosis, we designed a rat model with advanced liver fibrosis and cell model with an initial fibrotic stage. Model rats induced by CCl4 and alcohol presented advanced liver fibrosis with complete fibrous septa. The administration of curcumol (25 mg/kg or 50 mg/kg) resulted in reversal of liver fibrosis. Leptin-administrated liver sinusoidal endothelial cells presented defenestration and basement membrane components deposition, including laminin (LN) and type IV collagen (Col IV), the characteristics of capillarization by scanning electron microscopy and immunofluorescence assays. After treatment with curcumol (12.5, 25, or 50 mg/L), defenestration was restored and the levels of LN and Col IV were decreased, consistent with the rat model. Quantitative polymerase chain reaction and Western blot results revealed that increased levels of urokinase plasminogen activator (uPA)/ uPA receptor (uPAR) were observed both in vivo and in vitro, curcumol significantly reduced uPA/uPAR at both the mRNA and protein levels. Reduction of uPA/uPAR may be synergistic with matrix metallopeptidase 13 to reverse liver fibrogenesis. In conclusion, curcumol protects liver from phenotypic changes in the early and advanced fibrogenesis, possibly through uPA/uPAR pathway.

Jak Inhibition Prevents Bleomycin-Induced Fibrosis in Mice and Is Effective in Patients with Morphea

Jak Inhibition Prevents Bleomycin-Induced Fibrosis in Mice and Is Effective in Patients with Morphea

Collagenase loaded chitosan nanoparticles for digestion of the collagenous scar in liver fibrosis: The effect of chitosan intrinsic collagen binding on the success of targeting

A variety of hepatic insults result in the accumulation of collagen-rich new extracellular matrix in the liver, ultimately culminating in liver fibrosis and cirrhosis. For such reasons, approaches looking into digestion of the collagen-rich extracellular matrix present an interesting therapeutic approach for cases of chronic liver disease, where the fibrotic scar is well established. Portal collagenase administration has recently led to the successful reversion of cirrhosis in an experimental rabbit model. Notwithstanding, the question of how such a sensitive therapeutic macromolecule could be administered in a less invasive manner, and in a way that preserves its functionality and avoids digestion of other non-hepatic vital collagen presents itself. Chitosan is a biodegradable polymer that has been reported to interact and bind to collagen. Chitosan nanoparticles (CS NPs) have also been reported to encapsulate therapeutic proteins, maintaining their functional form and protecting them from in-vivo degradation. For such reasons, CS NPs were loaded with collagenase and evaluated in-vitro and in-vivo for their ability to target and digest collagen. CS NPs were able to encapsulate collagenase (≈ 60% encapsulation efficiency) and release its content in active form. To determine whether chitosan’s collagen interaction would enable NP collagen binding or whether the modification with collagen binding peptides (CBPs) is necessary, CS NPs were modified with the CBP; CCQDSETRTFY. Since the density of targeting ligand and the length of tether play a significant role in the success of active targeting, the surface of NPs was modified with different densities of the CBP either directly or using a polyethylene glycol (PEG) spacer. PEGylated NPs showed higher levels of CBP tagging; high, intermediate and low density of CBPs corresponded to 585.8 ± 33, 252.9 ± 25.3 and 56.5 ± 8.8 µg/mL for PEGylated NPs and 425.56 ± 12.67, 107.91 ± 10.3 and 49.86 ± 3.2 µg/mL for unPEGylated NPs, respectively. In-vitro collagen binding experiments showed that unmodified CS NPs were able to bind collagen and that modification with CBPs either directly or via PEG did not enhance collagen binding. In-vivo experiments demonstrated that unmodified CS NPs were able to reverse fibrosis with a survival rate of 100% at the end of the study, indicating the ability of CS NPs to deliver functional collagenase to the fibrotic liver and making the use of CBPs unnecessary.

Pulmonary Fibrosis and Its Related Factors in Discharged Patients with New Coronavirus Pneumonia: A Cohort Study of 90-150 Days Follow-Up after Onset

Background: The Coronavirus Disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic, posing a serious threat to public health worldwide. Whether survivors of COVID-19 pneumonia may be at risk of pulmonary fibrosis is still unknown.Methods: This study involves 462 laboratory confirmed patients with COVID-19 who were admitted to Shenzhen Third People’s Hospital. A total of 457 patients underwent thin-section chest CT scans during the hospitalization or after discharge to identify the pulmonary lesion. A total of 287 patients were followed up from 90 days to 150 days after the onset of the disease.Finding: 397 (86.87%), 311 (74.40%), 222 (79.56%), 141 (68.12%) and 49 (62.03%) patients developed with pulmonary fibrosis during the 0-30, 31-60, 61-90, 91-120 and >120 days after onset, respectively. Reversal of pulmonary fibrosis were found in 18 (4.53%), 61 (19.61%), 40 (18.02%), 54 (38.30%) and 24 (48.98%) COVID-19 patients during the 0-30, 31-60, 61-90, 91-120 and >120 days after onset, respectively. It was observed that Age, BMI, Fever, and Highest PCT were predictive factors for sustaining fibrosis even after 90 days from onset. Only a fraction of COVID-19 patients suffered with abnormal lung function after 90 days from onset.Interpretation: Long-term pulmonary fibrosis was more likely to develop in patients with older age, high BMI, severe/critical condition, fever, long time to turn the viral RNA negative, pre-existing disease and delay to admission. Fibrosis developed in COVID-19 patients could be reversed in about a half of the patients after 120 days from onset. The pulmonary function of most of COVID-19 patients with pulmonary fibrosis could turn to normal condition after three months from onset.Funding Statement: Shenzhen Science and Technology Research and Development Project (202002073000001 and 202002073000002), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP011).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: This study was conducted at Shenzhen Third People's Hospital and approved by the Ethics Committees, each patient gave written informed consent.

Inhibition of tyrosine kinase receptor signaling attenuates fibrogenesis in an ex vivo model of human renal fibrosis.

Poor translation from animal studies to human clinical trials is one of the main hurdles in the development of new drugs. Here, we used precision-cut kidney slices (PCKS) as a translational model to study renal fibrosis and to investigate whether inhibition of tyrosine kinase receptors, with the selective inhibitor nintedanib, can halt fibrosis in murine and human PCKS. We used renal tissue of murine and human origins to obtain PCKS. Control slices and slices treated with nintedanib were studied to assess viability, activation of tyrosine kinase receptors, cell proliferation, collagen type I accumulation, and gene and protein regulation. During culture, PCKS spontaneously develop a fibrotic response that resembles in vivo fibrogenesis. Nintedanib blocked culture-induced phosphorylation of platelet-derived growth factor receptor and vascular endothelial growth factor receptor. Furthermore, nintedanib inhibited cell proliferation and reduced collagen type I accumulation and expression of fibrosis-related genes in healthy murine and human PCKS. Modulation of extracellular matrix homeostasis was achieved already at 0.1 μM, whereas high concentrations (1 and 5 μM) elicited possible nonselective effects. In PCKS from human diseased renal tissue, nintedanib showed limited capacity to reverse established fibrosis. In conclusion, nintedanib attenuated the onset of fibrosis in both murine and human PCKS by inhibiting the phosphorylation of tyrosine kinase receptors; however, the reversal of established fibrosis was not achieved.