scholarly journals Stiffening of the Extracellular Matrix is a Sufficient Condition for Airway Hyperreactivity

2020 ◽  
Author(s):  
Ryan R Jamieson ◽  
Suzanne E Stasiak ◽  
Samuel R Polio ◽  
Jeffrey W Ruberti ◽  
Harikrishnan Parameswaran
Keyword(s):  
Extracellular Matrix ◽  
Low Dose ◽  
Muscle Force ◽  
Pathological Change ◽  
Fold Increase ◽  
Airway Hyperreactivity ◽  
Matrix Remodeling ◽  
Ultraviolet A ◽  
Therapeutic Approaches ◽  
Target Matrix

AbstractThe current therapeutic approach to asthma focuses exclusively on targeting inflammation and reducing airway smooth muscle force in an effort to prevent the recurrence of symptoms. However, the treatment is not a cure and has little beneficial effect on the progression of asthma. This suggests that there are mechanisms at play that are likely triggered by inflammation and eventually become self-sustaining so that even when airway inflammation is brought back under control, these alternative mechanisms continue to drive airway hyperreactivity in asthmatics. In this study, we hypothesized that the stiffening of the airway extracellular matrix is a core pathological change sufficient to support excessive bronchoconstriction in asthmatics even when in the absence of inflammation. To test this hypothesis, we increased the stiffness of airway ECM by photo-crosslinking collagen fibers within the airway wall using riboflavin (vitamin B2) and Ultraviolet-A radiation. In our experiments, collagen crosslinking led to a three-fold increase in stiffness of the airway extracellular matrix. This change was sufficient to cause airways to constrict to a greater degree, at a faster rate when exposed to a low dose of contractile agonist. Our results highlight the need for therapeutic approaches that target matrix remodeling to develop a lasting cure for this disease.

scholarly journals Stiffening of the Extracellular Matrix is a Sufficient Condition for Airway Hyperreactivity.

2021 ◽  
Author(s):  
Ryan R. Jamieson ◽  
Suzanne E. Stasiak ◽  
Samuel R. Polio ◽  
Ralston D. Augspurg ◽  
Caroline A. McCormick ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Low Dose ◽  
Muscle Force ◽  
Pathological Change ◽  
Fold Increase ◽  
Airway Hyperreactivity ◽  
Airway Wall ◽  
Ultraviolet A ◽  
Collagen Crosslinking ◽  
Airway Constriction

The current therapeutic approach to asthma focuses exclusively on targeting inflammation and reducing airway smooth muscle force to prevent the recurrence of symptoms. However, even when inflammation is brought under control, airways in an asthmatic can still hyper-constrict when exposed to a low dose of agonist. This suggests that there are mechanisms at play that are likely triggered by inflammation and eventually become self-sustaining so that even when airway inflammation is brought back under control, these alternative mechanisms continue to drive airway hyperreactivity in asthmatics. In this study, we hypothesized that stiffening of the airway extracellular matrix is a core pathological change sufficient to support excessive bronchoconstriction even in the absence of inflammation. To test this hypothesis, we increased the stiffness of airway extracellular matrix by photo-crosslinking collagen fibers within the airway wall of freshly dissected bovine rings using riboflavin (vitamin B2) and Ultraviolet-A radiation. In our experiments, collagen crosslinking led to a two-fold increase in the stiffness of the airway extracellular matrix. This change was sufficient to cause airways to constrict to a greater degree, and at a faster rate when they were exposed to 10-5M acetylcholine for 5 minutes. Our results show that stiffening of the extracellular matrix is sufficient to drive excessive airway constriction even in the absence of inflammatory signals.

scholarly journals Targeting Myeloid-Derived Suppressor Cells for Premetastatic Niche Disruption After Tumor Resection

2020 ◽  
Author(s):  
Fan Tang ◽  
Yan Tie ◽  
Weiqi Hong ◽  
Yuquan Wei ◽  
Chongqi Tu ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Low Dose ◽  
Surgical Stress ◽  
Suppressor Cells ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Myeloid Derived Suppressor Cells ◽  
Term Survival ◽  
Premetastatic Niche

AbstractSurgical resection is a common therapeutic option for primary solid tumors. However, high cancer recurrence and metastatic rates after resection are the main cause of cancer related mortalities. This implies the existence of a “fertile soil” following surgery that facilitates colonization by circulating cancer cells. Myeloid-derived suppressor cells (MDSCs) are essential for premetastatic niche formation, and may persist in distant organs for up to 2 weeks after surgery. These postsurgical persistent lung MDSCs exhibit stronger immunosuppression compared with presurgical MDSCs, suggesting that surgery enhances MDSC function. Surgical stress and trauma trigger the secretion of systemic inflammatory cytokines, which enhance MDSC mobilization and proliferation. Additionally, damage associated molecular patterns (DAMPs) directly activate MDSCs through pattern recognition receptor-mediated signals. Surgery also increases vascular permeability, induces an increase in lysyl oxidase and extracellular matrix remodeling in lungs, that enhances MDSC mobilization. Postsurgical therapies that inhibit the induction of premetastatic niches by MDSCs promote the long-term survival of patients. Cyclooxygenase-2 inhibitors and β-blockade, or their combination, may minimize the impact of surgical stress on MDSCs. Anti-DAMPs and associated inflammatory signaling inhibitors also are potential therapies. Existing therapies under tumor-bearing conditions, such as MDSCs depletion with low-dose chemotherapy or tyrosine kinase inhibitors, MDSCs differentiation using all-trans retinoic acid, and STAT3 inhibition merit clinical evaluation during the perioperative period. In addition, combining low-dose epigenetic drugs with chemokine receptors, reversing immunosuppression through the Enhanced Recovery After Surgery protocol, repairing vascular leakage, or inhibiting extracellular matrix remodeling also may enhance the long-term survival of curative resection patients.

scholarly journals Pathobiochemistry of arthrofibrotic remodeling

2017 ◽  
Vol 5 (4_suppl4) ◽  
pp. 2325967117S0015
Author(s):  
Isabel Faust ◽  
Philipp Traut ◽  
Cornelius Knappe ◽  
Doris Hendig
Keyword(s):  
Extracellular Matrix ◽  
Cardiac Fibrosis ◽  
Mechanical Strain ◽  
Inflammatory Cells ◽  
Scar Tissue ◽  
Proteoglycan Synthesis ◽  
Synthesis Rate ◽  
Matrix Remodeling ◽  
Therapeutic Approaches ◽  
Extracellular Matrix Components

Aims and Objectives: Arthrofibrosis is defined as painful impairment of joint flexibility due to fibrotic tissue remodeling after joint trauma or surgery. The incidence of arthrofibrosis after knee replacement surgery is 5 to 10%. Although conventional therapeutic approaches as for instance mobilization and physiotherapy are applied, an effective and causative therapeutic regimen is not known. Materials and Methods: To characterize arthrofibrotic remodeling of the extracellular matrix, to develop new therapeutic approaches and to define diagnostic biomarkers and therapeutic targets, understanding of biochemical principles is urgently required. Fibrotic remodeling was described in several tissues, whereas synovial fibrosis is one of the least investigated fibrotic disorders. Nevertheless, molecular key events in fibrosis seem to be the same and are initiated by exogenic or endogenic tissue damage and differentiation of resident fibroblasts of the connective tissue to myofibroblasts. Known inductors of myofibroblast differentiation are fibrotic growth factors, which are secreted by platelets, damaged tissue and inflammatory cells, as well as mechanical strain. Research studies concerning cardiac fibrosis in tako-tsubo cardiomyopathy also define emotional stress and sympathicotonic destabilization as profibrotic stressors. Myofibroblasts generate contractile forces and synthesize extracellular matrix components, so that scar tissue accumulates. While myofibroblasts disappear by apoptosis in physiological wound healing, they persist in fibrosis. Results: Recently, we could demonstrate that increased expression of human xylosyltransferase (XT)-I, an enzyme which catalyzes the rate limiting step in proteoglycan glycosylation, is linked to abnormal extracellular matrix remodeling. Serum XT activity reflects proteoglycan synthesis rate and is known as fibrosis biomarker in liver fibrosis or scleroderma. Our data also indicate that XT-I is a cellular key mediator of arthrofibrosis. However, we suggest that molecular changes based on arthrofibrosis are, due to local restriction of the affected joint by the blood-synovial-barrier, not detectable in human serum. Currently, we study synovial XT activity of arthrofibrosis patients and controls in a multicenter study. Conclusion: In summary, we give insights into the complex pathobiochemistry of arthrofibrosis as well as current research projects. A deeper characterization of the involved mechanisms might not only contribute to control and inhibit fibrotic remodeling by interfering with components of fibrotic signal cascades but also to establish new therapeutic strategies.

scholarly journals Implications of Skeletal Muscle Extracellular Matrix Remodeling in Metabolic Disorders: Diabetes Perspective

2020 ◽  
Vol 21 (11) ◽  
pp. 3845 ◽  
Author(s):  
Khurshid Ahmad ◽  
Inho Choi ◽  
Yong-Ho Lee
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Matrix Remodeling ◽  
Therapeutic Approaches ◽  
Ecm Remodeling ◽  
Metabolic Dysregulation ◽  
Pathological Conditions ◽  
Insulin Activity

The extracellular matrix (ECM) provides a scaffold for cells, controlling biological processes and providing structural as well as mechanical support to surrounding cells. Disruption of ECM homeostasis results in several pathological conditions. Skeletal muscle ECM is a complex network comprising collagens, proteoglycans, glycoproteins, and elastin. Recent therapeutic approaches targeting ECM remodeling have been extensively deliberated. Various ECM components are typically found to be augmented in the skeletal muscle of obese and/or diabetic humans. Skeletal muscle ECM remodeling is thought to be a feature of the pathogenic milieu allied with metabolic dysregulation, obesity, and eventual diabetes. This narrative review explores the current understanding of key components of skeletal muscle ECM and their specific roles in the regulation of metabolic diseases. Additionally, we discuss muscle-specific integrins and their role in the regulation of insulin sensitivity. A better understanding of the importance of skeletal muscle ECM remodeling, integrin signaling, and other factors that regulate insulin activity may help in the development of novel therapeutics for managing diabetes and other metabolic disorders.

Annexin II mediates plasminogen-dependent matrix invasion by human monocytes: enhanced expression by macrophages

Blood ◽  
2004 ◽  
Vol 103 (1) ◽  
pp. 317-324 ◽  
Author(s):  
Carrie Brownstein ◽  
Arunkumar B. Deora ◽  
Andrew T. Jacovina ◽  
Rebecca Weintraub ◽  
Menard Gertler ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Surface ◽  
Human Peripheral Blood ◽  
Fold Increase ◽  
Annexin Ii ◽  
Matrix Remodeling ◽  
Human Monocytes ◽  
Tail Domain ◽  
Blood Monocytes ◽  
Monocyte Migration

Abstract Monocytes and macrophages participate in a wide variety of host defense mechanisms. Annexin II, a fibrinolytic receptor, binds plasminogen and tissue plasminogen activator (t-PA) independently at the cell surface, thereby enhancing the catalytic efficiency of plasmin production. We demonstrated previously that annexin II on the surface of both cultured monocytoid cells and monocyte-derived macrophages promotes their ability to remodel extracellular matrix. Here, we demonstrate that human peripheral blood monocytes represent the major circulating annexin II–expressing cell. Annexin II supported t-PA–dependent generation of cell surface plasmin and the matrix-penetrating activity of human monocytes. Compared to polymorphonuclear leukocytes, monocytes supported a 12.9-fold greater rate of plasmin generation in the presence of exogenous t-PA, and this activity was largely attributable to annexin II. Likewise, anti–annexin II IgG directed against the t-PA–binding tail domain inhibited plasminogen-dependent, cytokine-directed monocyte migration through extracellular matrix. On differentiation of monocytes to macrophages, there was a 2.4-fold increase in annexin II–specific mRNA, and a 7.9-fold increase in surface annexin II. Thioglycolate-elicited peritoneal macrophages, furthermore, displayed an additional 3.8-fold increase in annexin II surface expression compared with resident cells. Thus, annexin II–mediated assembly of plasminogen and t-PA on monocyte/macrophages contributes to plasmin generation, matrix remodeling, and directed migration.

scholarly journals The Dynamic Interaction between Extracellular Matrix Remodeling and Breast Tumor Progression

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1046
Author(s):  
Jorge Martinez ◽  
Patricio C. Smith
Keyword(s):  
Extracellular Matrix ◽  
Type I Collagen ◽  
Cell Metabolism ◽  
Breast Tumors ◽  
Extracellular Matrix Remodeling ◽  
Type I ◽  
Matrix Remodeling ◽  
Desmoplastic Reaction ◽  
The Impact

Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.

scholarly journals Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Wei Dai ◽  
Shenglan Liu ◽  
Shubo Wang ◽  
Li Zhao ◽  
Xiao Yang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Uveal Melanoma ◽  
Specific Inhibitor ◽  
Type I ◽  
Matrix Remodeling ◽  
Metastatic Colonization ◽  
Tgf Β1

AbstractColonization is believed a rate-limiting step of metastasis cascade. However, its underlying mechanism is not well understood. Uveal melanoma (UM), which is featured with single organ liver metastasis, may provide a simplified model for realizing the complicated colonization process. Because DDR1 was identified to be overexpressed in UM cell lines and specimens, and abundant pathological deposition of extracellular matrix collagen, a type of DDR1 ligand, was noted in the microenvironment of liver in metastatic patients with UM, we postulated the hypothesis that DDR1 and its ligand might ignite the interaction between UM cells and their surrounding niche of liver thereby conferring strengthened survival, proliferation, stemness and eventually promoting metastatic colonization in liver. We tested this hypothesis and found that DDR1 promoted these malignant cellular phenotypes and facilitated metastatic colonization of UM in liver. Mechanistically, UM cells secreted TGF-β1 which induced quiescent hepatic stellate cells (qHSCs) into activated HSCs (aHSCs) which secreted collagen type I. Such a remodeling of extracellular matrix, in turn, activated DDR1, strengthening survival through upregulating STAT3-dependent Mcl-1 expression, enhancing stemness via upregulating STAT3-dependent SOX2, and promoting clonogenicity in cancer cells. Targeting DDR1 by using 7rh, a specific inhibitor, repressed proliferation and survival in vitro and in vivo outgrowth. More importantly, targeting cancer cells by pharmacological inactivation of DDR1 or targeting microenvironmental TGF-β1-collagen I loop exhibited a prominent anti-metastasis effect in mice. In conclusion, targeting DDR1 signaling and TGF-β signaling may be a novel approach to diminish hepatic metastasis in UM.

scholarly journals Low-dose IL-2 therapy limits the reduction in absolute numbers of circulating regulatory T cells in rheumatoid arthritis

2021 ◽  
Vol 13 ◽  
pp. 1759720X2110113
Author(s):  
Sheng-Xiao Zhang ◽  
Jia Wang ◽  
Cai-Hong Wang ◽  
Rui-Huan Jia ◽  
Ming Yan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Side Effects ◽  
Regulatory T Cells ◽  
Disease Activity ◽  
Immune Tolerance ◽  
Low Dose ◽  
Fold Increase ◽  
Plain Language ◽  
T Subsets

Background: Circulating regulatory T cells (Tregs) are responsible for mediating immune tolerance and maintaining immunological homeostasis. Decreases in Tregs may be involved in the onset of rheumatoid arthritis (RA). Low-dose interleukin-2 (IL-2) has been considered for the treatment of inflammatory diseases mediated by T cells. This study focused on the status of circulating CD4+T subsets and the clinical feasibility of IL-2 therapies in patients with RA. Methods: The subjects included 888 patients with RA and 100 healthy controls (HCs); 233 RA patients received IL-2 treatment with 0.5 million international units (MIU)/day from days 1 through 5. The demographic features, disease activity, and levels of CD4+T cells measured by modified flow cytometry were collected in all RA patients before and after treatment. Results: RA patients had lower absolute Treg counts (but not Th17) compared with HCs, which was associated with disease activity; previously treated RA patients had the fewest circulating Tregs ( p < 0.05). Patients treated with low-dose IL-2 had a three-fold increase in absolute anti-inflammatory Treg counts, as well as a two-fold increase in the other CD4+T subsets. Moreover, post-treatment levels of markers of disease activity in RA patients treated with IL-2 were significantly lower than the baseline values ( p < 0.001), with no apparent side effects. Conclusion: Decreased absolute counts of circulating CD4+T lymphocyte subsets were observed in patients with RA. Circulating Tregs, which mediate immune tolerance, may be involved in the pathogenesis and progression of RA; however, this was ameliorated by low-dose IL-2, without obvious side effects. Plain language summary Low-dose IL-2 treatment for rheumatoid arthritis • Circulating Tregs may be involved in the pathogenesis and progression of RA. • The absolute count of Tregs was significantly correlated with disease activity measures. • Low-dose IL-2 was able to effectively expade Tregs and help for RA patients’ symptoms remission without evaluated side effects.

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