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Richard H Gomer - One of the best experts on this subject based on the ideXlab platform.
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reduced sialylation and bioactivity of the antifibrotic protein serum amyloid p in the sera of patients with idiopathic pulmonary fibrosis
ImmunoHorizons, 2020Co-Authors: Wensheng Chen, Erica L Herzog, Tejas R. Karhadkar, Changwan Ryu, Richard H GomerAbstract:Pulmonary fibrosis is a chronic and generally fatal disorder characterized by progressive formation of scar-like tissue in the lungs. Sialic acids are often found as the terminal sugar on extracellular glycoconjugates such as protein glycosylations. Sialidases, also known as neuraminidases, desialylate glycoconjugates. Serum amyloid P (SAP), a pentameric serum glycoprotein that has two sialic acids on each polypeptide, inhibits the differentiation of monocytes into Fibrocytes and promotes human PBMCs to accumulate high extracellular levels of IL-10. When SAP is desialylated with sialidase, the effects of SAP on Fibrocyte differentiation and IL-10 accumulation are strongly inhibited. Intriguingly, in patients with pulmonary fibrosis, there are increased levels of sialidase activity in the bronchoalveolar lavage fluid, increased levels of sialidases in the lungs, and decreased levels of SAP in the sera. To elucidate the role of SAP desialylation in idiopathic pulmonary fibrosis (IPF) pathogenesis, we purified SAP from the serum of IPF patients and healthy controls and measured the extent of sialylation and bioactivity of the purified SAP. We find that some IPF patients have abnormally high levels of the sialidase NEU3 in their sera and that the SAP in the sera of IPF patients has an abnormally high extent of desialylation and an abnormally low ability to inhibit Fibrocyte differentiation and induce extracellular IL-10 accumulation by PBMC. These results suggest that SAP desialylation may play a role in IPF pathogenesis and that inhibiting NEU3 could be a potential therapeutic target for IPF.
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Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model
Scientific Reports, 2017Co-Authors: Tejas R. Karhadkar, Darrell Pilling, Nehemiah Cox, Richard H GomerAbstract:Fibrosis involves increasing amounts of scar tissue appearing in a tissue, but what drives this is unclear. In fibrotic lesions in human and mouse lungs, we found extensive desialylation of glycoconjugates, and upregulation of sialidases. The fibrosis-associated cytokine TGF-β1 upregulates sialidases in human airway epithelium cells, lung fibroblasts, and immune system cells. Conversely, addition of sialidases to human peripheral blood mononuclear cells induces accumulation of extracellular TGF-β1, forming what appears to be a sialidase - TGF-β1 - sialidase positive feedback loop. Monocyte-derived cells called Fibrocytes also activate fibroblasts, and we found that sialidases potentiate Fibrocyte differentiation. A sialylated glycoprotein called serum amyloid P (SAP) inhibits Fibrocyte differentiation, and sialidases attenuate SAP function. Injections of the sialidase inhibitors DANA and oseltamivir (Tamiflu) starting either 1 day or 10 days after bleomycin strongly attenuate pulmonary fibrosis in the mouse bleomycin model, and by breaking the feedback loop, cause a downregulation of sialidase and TGF-β1 accumulation. Together, these results suggest that a positive feedback loop involving sialidases potentiates fibrosis, and suggest that sialidase inhibitors could be useful for the treatment of fibrosis.
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RESEARCH ARTICLE
2016Co-Authors: Thrombin Polarize, Michael J V White, Macrophages Towards A Pro-fibrotic, Richard H GomerAbstract:For both wound healing and the formation of a fibrotic lesion, circulating monocytes enter the tissue and differentiate into fibroblast-like cells called Fibrocytes and pro-fibrotic M2a macrophages, which together with fibroblasts form scar tissue. Monocytes can also differ-entiate into classically activated M1 macrophages and alternatively activated M2 macro-phages. The proteases thrombin, which is activated during blood clotting, and tryptase, which is released by activated mast cells, potentiate fibroblast proliferation and Fibrocyte dif-ferentiation, but their effect on macrophages is unknown. Here we report that thrombin, tryp-tase, and the protease trypsin bias human macrophage differentiation towards a pro-fibrotic M2a phenotype expressing high levels of galectin-3 from unpolarized monocytes, or from M1 and M2 macrophages, and that these effects appear to operate through protease-acti-vated receptors. These results suggest that proteases can initiate scar tissue formation by affecting fibroblasts, Fibrocytes, and macrophages
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peritoneal dialysis fluid and some of its components potentiate Fibrocyte differentiation
Peritoneal Dialysis International, 2016Co-Authors: Sarah E Herlihy, Nehemiah Cox, Hannah E Starke, Melisa Lopezanton, Katayoon Keyhanian, Donald James Fraser, Richard H GomerAbstract:Long-term peritoneal dialysis (PD) often results in the development of peritoneal fibrosis. In many other fibrosing diseases, monocytes enter the fibrotic lesion and differentiate into fibroblast-like cells called Fibrocytes. We find that peritoneal tissue from short-term PD patients contains few Fibrocytes, while Fibrocytes are readily observed in the peritoneal membrane of long-term PD patients. The PD fluid Dianeal (Baxter Healthcare Corporation, Deerfield, IL, USA) contains dextrose, a number of electrolytes including sodium chloride, and sodium lactate. We find that PD fluid potentiates human Fibrocyte differentiation in vitro and implicates sodium lactate in this potentiation. The plasma protein serum amyloid P (SAP) inhibits Fibrocyte differentiation. Peritoneal dialysis fluid and sodium chloride decrease the ability of human SAP to inhibit human Fibrocyte differentiation in vitro Together, these results suggest that PD fluid contributes to the development of peritoneal fibrosis by potentiating Fibrocyte differentiation.
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tnf α stimulated fibroblasts secrete lumican to promote Fibrocyte differentiation
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Darrell Pilling, Varsha Vakil, Richard H GomerAbstract:In healing wounds and fibrotic lesions, fibroblasts and monocyte-derived fibroblast-like cells called Fibrocytes help to form scar tissue. Although Fibrocytes promote collagen production by fibroblasts, little is known about signaling from fibroblasts to Fibrocytes. In this report, we show that fibroblasts stimulated with the Fibrocyte-secreted inflammatory signal tumor necrosis factor-α secrete the small leucine-rich proteoglycan lumican, and that lumican, but not the related proteoglycan decorin, promotes human Fibrocyte differentiation. Lumican competes with the serum Fibrocyte differentiation inhibitor serum amyloid P, but dominates over the fibroblast-secreted Fibrocyte inhibitor Slit2. Lumican acts directly on monocytes, and unlike other factors that affect Fibrocyte differentiation, lumican has no detectable effect on macrophage differentiation or polarization. α2β1, αMβ2, and αXβ2 integrins are needed for lumican-induced Fibrocyte differentiation. In lung tissue from pulmonary fibrosis patients with relatively normal lung function, lumican is present at low levels throughout the tissue, whereas patients with advanced disease have pronounced lumican expression in the fibrotic lesions. These data may explain why Fibrocytes are increased in fibrotic tissues, suggest that the levels of lumican in tissues may have a significant effect on the decision of monocytes to differentiate into Fibrocytes, and indicate that modulating lumican signaling may be useful as a therapeutic for fibrosis.
Darrell Pilling - One of the best experts on this subject based on the ideXlab platform.
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Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model
Scientific Reports, 2017Co-Authors: Tejas R. Karhadkar, Darrell Pilling, Nehemiah Cox, Richard H GomerAbstract:Fibrosis involves increasing amounts of scar tissue appearing in a tissue, but what drives this is unclear. In fibrotic lesions in human and mouse lungs, we found extensive desialylation of glycoconjugates, and upregulation of sialidases. The fibrosis-associated cytokine TGF-β1 upregulates sialidases in human airway epithelium cells, lung fibroblasts, and immune system cells. Conversely, addition of sialidases to human peripheral blood mononuclear cells induces accumulation of extracellular TGF-β1, forming what appears to be a sialidase - TGF-β1 - sialidase positive feedback loop. Monocyte-derived cells called Fibrocytes also activate fibroblasts, and we found that sialidases potentiate Fibrocyte differentiation. A sialylated glycoprotein called serum amyloid P (SAP) inhibits Fibrocyte differentiation, and sialidases attenuate SAP function. Injections of the sialidase inhibitors DANA and oseltamivir (Tamiflu) starting either 1 day or 10 days after bleomycin strongly attenuate pulmonary fibrosis in the mouse bleomycin model, and by breaking the feedback loop, cause a downregulation of sialidase and TGF-β1 accumulation. Together, these results suggest that a positive feedback loop involving sialidases potentiates fibrosis, and suggest that sialidase inhibitors could be useful for the treatment of fibrosis.
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role of neoplastic monocyte derived Fibrocytes in primary myelofibrosis
Journal of Experimental Medicine, 2016Co-Authors: Srdan Verstovsek, Darrell Pilling, Taghi Manshouri, Carlos E Buesoramos, Kate J Newberry, Sanja Prijic, Liza Knez, Ksenija Bozinovic, David Harris, Erika L SpaethAbstract:Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with monocyte-derived Fibrocytes. Therefore, we sought to determine whether Fibrocytes play a role in the induction of BM fibrosis in PMF. In this study, we show that BM from patients with PMF harbors an abundance of clonal, neoplastic collagen- and fibronectin-producing Fibrocytes. Immunodeficient mice transplanted with myelofibrosis patients' BM cells developed a lethal myelofibrosis-like phenotype. Treatment of the xenograft mice with the Fibrocyte inhibitor serum amyloid P (SAP; pentraxin-2) significantly prolonged survival and slowed the development of BM fibrosis. Collectively, our data suggest that neoplastic Fibrocytes contribute to the induction of BM fibrosis in PMF, and inhibiting Fibrocyte differentiation with SAP may interfere with this process.
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tnf α stimulated fibroblasts secrete lumican to promote Fibrocyte differentiation
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Darrell Pilling, Varsha Vakil, Richard H GomerAbstract:In healing wounds and fibrotic lesions, fibroblasts and monocyte-derived fibroblast-like cells called Fibrocytes help to form scar tissue. Although Fibrocytes promote collagen production by fibroblasts, little is known about signaling from fibroblasts to Fibrocytes. In this report, we show that fibroblasts stimulated with the Fibrocyte-secreted inflammatory signal tumor necrosis factor-α secrete the small leucine-rich proteoglycan lumican, and that lumican, but not the related proteoglycan decorin, promotes human Fibrocyte differentiation. Lumican competes with the serum Fibrocyte differentiation inhibitor serum amyloid P, but dominates over the fibroblast-secreted Fibrocyte inhibitor Slit2. Lumican acts directly on monocytes, and unlike other factors that affect Fibrocyte differentiation, lumican has no detectable effect on macrophage differentiation or polarization. α2β1, αMβ2, and αXβ2 integrins are needed for lumican-induced Fibrocyte differentiation. In lung tissue from pulmonary fibrosis patients with relatively normal lung function, lumican is present at low levels throughout the tissue, whereas patients with advanced disease have pronounced lumican expression in the fibrotic lesions. These data may explain why Fibrocytes are increased in fibrotic tissues, suggest that the levels of lumican in tissues may have a significant effect on the decision of monocytes to differentiate into Fibrocytes, and indicate that modulating lumican signaling may be useful as a therapeutic for fibrosis.
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The long pentraxin PTX3 promotes Fibrocyte differentiation.
PLOS ONE, 2015Co-Authors: Darrell Pilling, Varsha Vakil, Nehemiah Cox, J. Sjef VerbeekAbstract:Monocyte-derived, fibroblast-like cells called Fibrocytes are associated with fibrotic lesions. The plasma protein serum amyloid P component (SAP; also known as pentraxin-2, PTX2) inhibits Fibrocyte differentiation in vitro, and injections of SAP inhibit fibrosis in vivo. SAP is a member of the pentraxin family of proteins that includes C-reactive protein (CRP; PTX1) and pentraxin-3 (PTX3). All three pentraxins are associated with fibrosis, but only SAP and CRP have been studied for their effects on Fibrocyte differentiation. We find that compared to SAP and CRP, PTX3 promotes human and murine Fibrocyte differentiation. The effect of PTX3 is dependent on FcγRI. In competition studies, the Fibrocyte-inhibitory activity of SAP is dominant over PTX3. Binding competition studies indicate that SAP and PTX3 bind human FcγRI at different sites. In murine models of lung fibrosis, PTX3 is present in fibrotic areas, and the PTX3 distribution is associated with collagen deposition. In lung tissue from pulmonary fibrosis patients, PTX3 has a widespread distribution, both in unaffected tissue and in fibrotic lesions, whereas SAP is restricted to areas adjacent to vessels, and absent from fibrotic areas. These data suggest that the relative levels of SAP and PTX3 present at sites of fibrosis may have a significant effect on the ability of monocytes to differentiate into Fibrocytes.
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distinct fcγ receptors mediate the effect of serum amyloid p on neutrophil adhesion and Fibrocyte differentiation
Journal of Immunology, 2014Co-Authors: Nehemiah Cox, Darrell Pilling, Richard H GomerAbstract:The plasma protein serum amyloid P (SAP) reduces neutrophil adhesion, inhibits the differentiation of monocytes into fibroblast-like cells called Fibrocytes, and promotes phagocytosis of cell debris by macrophages. Together, these effects of SAP reduce key aspects of inflammation and fibrosis, and SAP injections improve lung function in pulmonary fibrosis patients. SAP functions are mediated, in part, by FcγRs, but the contribution of each FcγR is not fully understood. We found that aa Q55 and E126 in human SAP affect human Fibrocyte differentiation and SAP binding to FcγRI. E126, K130, and Q128 affect neutrophil adhesion and SAP affinity for FcγRIIa. Q128 also affects phagocytosis by macrophages and SAP affinity for FcγRI. All the identified functionally significant amino acids in SAP form a binding site that is distinct from the previously described SAP-FcγRIIa binding site. Blocking FcγRI with an IgG-blocking Ab reduces the SAP effect on Fibrocyte differentiation, and ligating FcγRIIa with Abs reduces neutrophil adhesion. Together, these results suggest that SAP binds to FcγRI on monocytes to inhibit Fibrocyte differentiation, and binds to FcγRIIa on neutrophils to reduce neutrophil adhesion.
Robert M. Strieter - One of the best experts on this subject based on the ideXlab platform.
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The Role of Fibrocytes in Sickle Cell Lung Disease
2016Co-Authors: Joshua J. Field, Marie D Burdick, Brett A Strieter, Ling Liu, Michael R. Debaun, Borna Mehrad, Edward C. Rose, Joel Linden, Robert M. StrieterAbstract:Background: Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived Fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of Fibrocytes to the pathogenesis of sickle cell lung disease. Methodology/Principal Findings: Fibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of Fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated Fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of Fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, Fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most Fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of Fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology
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circulating Fibrocytes correlate with bronchiolitis obliterans syndrome development after lung transplantation a novel clinical biomarker
The Annals of Thoracic Surgery, 2011Co-Authors: Damien J Lapar, Robert M. Strieter, Marie D Burdick, Abbas Emaminia, David A Harris, Brett A Strieter, Ling Liu, Mark K Robbins, Irving L Kron, Christine L LauAbstract:Background Development of bronchiolitis obliterans syndrome (BOS) after lung transplantation confers increased patient morbidity and mortality. Fibrocytes are circulating bone marrow–derived mesenchymal cell progenitors that influence tissue repair and fibrosis. Fibrocytes have been implicated in chronic pulmonary inflammatory processes. We investigated the correlation of circulating Fibrocyte number with BOS development in lung transplant patients. Methods We prospectively quantified circulating Fibrocyte levels among lung transplant patients. Patients were stratified according to the development of BOS as indicated by predicted forced expiratory volume in 1 second. Fibrocyte activity was analyzed by flow cytometry (cluster of differentiation 45 + , collagen 1 + ) in a blinded manner related to clinical presentation. Results Thirty-nine patients (61.5% men) underwent double (33.3%), left (25.6%), or right (41.0%) lung transplantation. Average patient age was similar between BOS and non-BOS patients (58.3 ± 3.9 vs 60.3 ± 2.0 years, p = 0.67). Chronic obstructive lung disease was the most common indication for lung transplantation (41.0%). Median forced expiratory volume in 1 second was lower among BOS patients compared with non-BOS patients (1.08 vs. 2.18 L/s, p = 0.001). Importantly, circulating Fibrocyte numbers were increased in BOS patients compared with non-BOS patients (8.91 vs 2.96 × 10 5 cells/mL, p = 0.03) by flow cytometry and were incrementally increased with advancing BOS stage ( p = 0.02). Conclusions Increased circulating Fibrocyte levels correlate with the development of BOS after lung transplantation and positively correlate with advancing BOS stage. Quantification of circulating Fibrocytes could serve as a novel biomarker and possible therapeutic target for BOS development in lung transplant patients.
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circulating Fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis
American Journal of Respiratory and Critical Care Medicine, 2009Co-Authors: A. Moeller, Sarah E Gilpin, Peter J Margetts, Colm Boylan, Jack Gauldie, Deborah J. Cook, Paul M Obyrne, Julian Dobranowski, Laszlo Farkas, Robert M. StrieterAbstract:Rationale: The clinical management of idiopathic pulmonary fibrosis (IPF) remains a major challenge due to lack of effective drug therapy or accurate indicators for disease progression. Fibrocytes are circulating mesenchymal cell progenitors that are involved in tissue repair and fibrosis.Objectives: To test the hypothesis that assay of these cells may provide a biomarker for activity and progression of IPF.Methods: Fibrocytes were defined as cells positive for CD45 and collagen-1 by flow cytometry and quantified in patients with stable IPF and during acute exacerbation of the disease. We investigated the clinical and prognostic value of Fibrocyte counts by comparison with standard clinical parameters and survival. We used healthy age-matched volunteers and patients with acute respiratory distress syndrome as control subjects.Measurements and Main Results: Fibrocytes were significantly elevated in patients with stable IPF (n = 51), with a further increase during acute disease exacerbation (n = 7; P < 0.00...
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differentiation of human circulating Fibrocytes as mediated by transforming growth factor β and peroxisome proliferator activated receptor γ
Journal of Biological Chemistry, 2007Co-Authors: Kurt Hong, Marie D Burdick, John A Belperio, Michael P Keane, Robert M. StrieterAbstract:Fibrocytes are a distinct population of fibroblast-like progenitor cells in peripheral blood that have recently been shown to possess plasticity to differentiate along mesenchymal lineages, including commitment to myofibroblast and adipocyte cells. Here, we demonstrated that transforming growth factor (TGF) β1 drives Fibrocyte-to-myofibroblast differentiation through activating Smad2/3 and SAPK/JNK MAPK pathways, which in turn stimulates α-smooth muscle actin expression. We determined that SAPK/JNK signaling acts in a positive feedback loop to modulate Smad2/3 nuclear availability and Smad2/3-dependent transcription. Conversely, Fibrocyte-to-adipocyte differentiation is driven by the peroxisome proliferator-activated receptor (PPAR) γ agonist troglitazone, which is associated with cytoplasmic lipid accumulation and induction of aP2. Treatment with troglitazone also disrupted TGFβ1-activated SAPK/JNK signaling, leading to decreased Smad2/3 transactivation activity and α-smooth muscle actin expression. Interestingly, TGFβ1 was demonstrated to have reciprocal inhibition on Fibrocyte differentiation to adipocytes. By activating SAPK/JNK signaling, which is normally suppressed during adipogenesis, PPARγ-dependent transactivation activity and induction of aP2 expression were disrupted. Taken together, within the context of the local microenvironmental niche, the delicate balance of PPARγ and TGFβ1 activation drives the selection of an adipocyte or myofibroblast differentiation pathway through SAPK/JNK signaling.
Nehemiah Cox - One of the best experts on this subject based on the ideXlab platform.
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Sialidase inhibitors attenuate pulmonary fibrosis in a mouse model
Scientific Reports, 2017Co-Authors: Tejas R. Karhadkar, Darrell Pilling, Nehemiah Cox, Richard H GomerAbstract:Fibrosis involves increasing amounts of scar tissue appearing in a tissue, but what drives this is unclear. In fibrotic lesions in human and mouse lungs, we found extensive desialylation of glycoconjugates, and upregulation of sialidases. The fibrosis-associated cytokine TGF-β1 upregulates sialidases in human airway epithelium cells, lung fibroblasts, and immune system cells. Conversely, addition of sialidases to human peripheral blood mononuclear cells induces accumulation of extracellular TGF-β1, forming what appears to be a sialidase - TGF-β1 - sialidase positive feedback loop. Monocyte-derived cells called Fibrocytes also activate fibroblasts, and we found that sialidases potentiate Fibrocyte differentiation. A sialylated glycoprotein called serum amyloid P (SAP) inhibits Fibrocyte differentiation, and sialidases attenuate SAP function. Injections of the sialidase inhibitors DANA and oseltamivir (Tamiflu) starting either 1 day or 10 days after bleomycin strongly attenuate pulmonary fibrosis in the mouse bleomycin model, and by breaking the feedback loop, cause a downregulation of sialidase and TGF-β1 accumulation. Together, these results suggest that a positive feedback loop involving sialidases potentiates fibrosis, and suggest that sialidase inhibitors could be useful for the treatment of fibrosis.
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peritoneal dialysis fluid and some of its components potentiate Fibrocyte differentiation
Peritoneal Dialysis International, 2016Co-Authors: Sarah E Herlihy, Nehemiah Cox, Hannah E Starke, Melisa Lopezanton, Katayoon Keyhanian, Donald James Fraser, Richard H GomerAbstract:Long-term peritoneal dialysis (PD) often results in the development of peritoneal fibrosis. In many other fibrosing diseases, monocytes enter the fibrotic lesion and differentiate into fibroblast-like cells called Fibrocytes. We find that peritoneal tissue from short-term PD patients contains few Fibrocytes, while Fibrocytes are readily observed in the peritoneal membrane of long-term PD patients. The PD fluid Dianeal (Baxter Healthcare Corporation, Deerfield, IL, USA) contains dextrose, a number of electrolytes including sodium chloride, and sodium lactate. We find that PD fluid potentiates human Fibrocyte differentiation in vitro and implicates sodium lactate in this potentiation. The plasma protein serum amyloid P (SAP) inhibits Fibrocyte differentiation. Peritoneal dialysis fluid and sodium chloride decrease the ability of human SAP to inhibit human Fibrocyte differentiation in vitro Together, these results suggest that PD fluid contributes to the development of peritoneal fibrosis by potentiating Fibrocyte differentiation.
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The long pentraxin PTX3 promotes Fibrocyte differentiation.
PLOS ONE, 2015Co-Authors: Darrell Pilling, Varsha Vakil, Nehemiah Cox, J. Sjef VerbeekAbstract:Monocyte-derived, fibroblast-like cells called Fibrocytes are associated with fibrotic lesions. The plasma protein serum amyloid P component (SAP; also known as pentraxin-2, PTX2) inhibits Fibrocyte differentiation in vitro, and injections of SAP inhibit fibrosis in vivo. SAP is a member of the pentraxin family of proteins that includes C-reactive protein (CRP; PTX1) and pentraxin-3 (PTX3). All three pentraxins are associated with fibrosis, but only SAP and CRP have been studied for their effects on Fibrocyte differentiation. We find that compared to SAP and CRP, PTX3 promotes human and murine Fibrocyte differentiation. The effect of PTX3 is dependent on FcγRI. In competition studies, the Fibrocyte-inhibitory activity of SAP is dominant over PTX3. Binding competition studies indicate that SAP and PTX3 bind human FcγRI at different sites. In murine models of lung fibrosis, PTX3 is present in fibrotic areas, and the PTX3 distribution is associated with collagen deposition. In lung tissue from pulmonary fibrosis patients, PTX3 has a widespread distribution, both in unaffected tissue and in fibrotic lesions, whereas SAP is restricted to areas adjacent to vessels, and absent from fibrotic areas. These data suggest that the relative levels of SAP and PTX3 present at sites of fibrosis may have a significant effect on the ability of monocytes to differentiate into Fibrocytes.
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distinct fcγ receptors mediate the effect of serum amyloid p on neutrophil adhesion and Fibrocyte differentiation
Journal of Immunology, 2014Co-Authors: Nehemiah Cox, Darrell Pilling, Richard H GomerAbstract:The plasma protein serum amyloid P (SAP) reduces neutrophil adhesion, inhibits the differentiation of monocytes into fibroblast-like cells called Fibrocytes, and promotes phagocytosis of cell debris by macrophages. Together, these effects of SAP reduce key aspects of inflammation and fibrosis, and SAP injections improve lung function in pulmonary fibrosis patients. SAP functions are mediated, in part, by FcγRs, but the contribution of each FcγR is not fully understood. We found that aa Q55 and E126 in human SAP affect human Fibrocyte differentiation and SAP binding to FcγRI. E126, K130, and Q128 affect neutrophil adhesion and SAP affinity for FcγRIIa. Q128 also affects phagocytosis by macrophages and SAP affinity for FcγRI. All the identified functionally significant amino acids in SAP form a binding site that is distinct from the previously described SAP-FcγRIIa binding site. Blocking FcγRI with an IgG-blocking Ab reduces the SAP effect on Fibrocyte differentiation, and ligating FcγRIIa with Abs reduces neutrophil adhesion. Together, these results suggest that SAP binds to FcγRI on monocytes to inhibit Fibrocyte differentiation, and binds to FcγRIIa on neutrophils to reduce neutrophil adhesion.
Chun Hua Wang - One of the best experts on this subject based on the ideXlab platform.
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oxygen desaturation is associated with Fibrocyte activation via epidermal growth factor receptor hypoxia inducible factor hif 1a axis in copd
European Respiratory Journal, 2019Co-Authors: Chun Hua Wang, Tzuting Huang, Kian Fan ChungAbstract:Background: Hypoxemia in COPD is often accompanied by progressive airflow obstruction that may be contributed by blood-borne progenitor Fibrocytes homing to disease site and differentiating into myofibroblasts. Aim: To investigate whether hypoxemia leads to the activation of Fibrocytes through epidermal growth factor receptor (EGFR) transactivation underlying the loss of lung function in hypoxemic COPD patients. Methods: COPD patients with hypoxemia (SpO2≤88%) at rest or exercise were defined as desaturators. Non-adherent non-T (NANT) cell fraction of peripheral blood mononuclear cells was isolated. Flow cytometry was used to determine collagen 1+/CD45+ Fibrocytes and α-SMA+ differentiating Fibrocytes within NANT cells and the expression of EGFR and hypoxia-inducible factor (HIF)-1α. Serum level of interleukin(IL)-8 was measured by ELISA. Results: Compared to COPD non-desaturators (n=12), COPD desaturators (n=14) had an increased number of circulating Fibrocytes, more rapid lung function decline, and elevated serum IL-8 levels. The percentage of Fibrocytes was positively correlated with yearly decline rate in FEV1 (r=-0.615, p=0.028). Fibrocytes from desaturators had a higher expression of EGFR and HIF-1α, a greater responsiveness to IL-8, and exaggerated capacity for proliferation and differentiation. Under hypoxia (5% oxygen), expression of EGFR and HIF-1α Fibrocytes fron non-desaturators was up-regulated. Inhibition of EGFR (by gefitinib) suppressed Fibrocyte proliferation and differentiation induced by hypoxia and IL-8. Conclusion: Hypoxemia triggers Fibrocyte activation through EGFR/HIF-1α axis, facilitating airflow obstruction in COPD.
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Reduced suppressive effect of β2-adrenoceptor agonist on Fibrocyte function in severe asthma
BMC, 2017Co-Authors: Charalambos Michaeloudes, Chun Hua Wang, Han Pin Kuo, Pankaj K. Bhavsar, Chien-da Huang, Po-jui Chang, Kian Fan ChungAbstract:Abstract Background Patients with severe asthma have increased airway remodelling and elevated numbers of circulating Fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β2-adrenergic receptor (AR) agonists (LABAs). We determined the effect of β2-AR agonists, alone or in combination with corticosteroids, on Fibrocyte function. Methods Non-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the β2-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone. The number of Fibrocytes (collagen I+/CD45+ cells) and differentiating Fibrocytes (α-smooth muscle actin+ cells), and the expression of CC chemokine receptor 7 and of β2-AR were determined using flow cytometry. The role of cyclic adenosine monophosphate (cAMP) was elucidated using the cAMP analogue 8-bromoadenosine 3′,5′-cyclic monophosphate (8-Br-cAMP) and the phosphodiesterase type IV (PDE4) inhibitor, rolipram. Results Salmeterol reduced the proliferation, myofibroblastic differentiation and CCR7 expression of Fibrocytes from healthy subjects and non-severe asthma patients. Fibrocytes from severe asthma patients had a lower baseline surface β2-AR expression and were relatively insensitive to salmeterol but not to 8-Br-cAMP or rolipram. Dexamethasone increased β2-AR expression and enhanced the inhibitory effect of salmeterol on severe asthma Fibrocyte differentiation. Conclusions Fibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids
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Additional file 5: Figure S4. of Reduced suppressive effect of β2-adrenoceptor agonist on Fibrocyte function in severe asthma
2017Co-Authors: Charalambos Michaeloudes, Chun Hua Wang, Han Pin Kuo, Chien-da Huang, Po-jui Chang, Pankaj Bhavsar, Kian ChungAbstract:Effect of ICI-118,551 on salmeterol-mediated reduction in Fibrocyte number and differentiation. NANT cells from healthy subjects (n = 6) were treated with salmeterol (10−8 M) in the presence or absence of ICI-118,551 (10−5 M) for 3 days. The number of Fibrocytes (Col I+/CD45+ cells; A) and differentiating Fibrocytes (α-SMA+ cells; B) was determined. Bars represent mean ± SEM.* p
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Fibrocyte trafficking in patients with chronic obstructive asthma and during an acute asthma exacerbation
The Journal of Allergy and Clinical Immunology, 2015Co-Authors: Chun Hua Wang, Tzuting Huang, Kian Fan Chung, T H Punde, Chien Da Huang, Pai Chien Chou, Chenghsien Liu, Han Pin KuoAbstract:Background Fibrocytes express several chemokine receptors (CCR7 and CXCR4) that regulate their recruitment and trafficking into tissue-damage sites in response to specific chemokine gradients (CCL19 and CXCL12). Objective We investigated whether these chemoattractants and S100A9, through the receptor for advanced glycation end-products (RAGE; ie, its receptor), are involved in Fibrocyte trafficking in patients with chronic obstructive asthma (COA) and during an acute exacerbation (AE) in patients without airflow obstruction (Asthma AE group). Methods We collected peripheral blood from 14 asthmatic patients with normal pulmonary function, 14 patients with COA, 11 patients in the Asthma AE group, and 14 healthy subjects. Isolated circulating Fibrocytes were used for migration assay. Expression of CCR7, CXCR4, S100A9, and RAGE in Fibrocytes was measured by using flow cytometry. CCL19 and CXCL12 expression in bronchial tissues was determined by using immunohistochemistry and RT-PCR. Results There were higher numbers of circulating Fibrocytes in patients in the Asthma AE group and patients with COA. The expression of CXCL12 in bronchial tissues and CXCR4 in circulating Fibrocytes was higher in the Asthma AE group and, to a lesser extent, in patients with COA. The expression of CCL19 in bronchial tissues and CCR7 in Fibrocytes was higher in patients with COA. CXCL12/CXCR4 and CCL19/CCR7 enhanced Fibrocyte transmigration in the Asthma AE group and in patients with COA, respectively. The upregulated expression of S100A9 and RAGE in Fibrocytes of patients in the Asthma AE group and those with COA contributes to the enhanced basal migratory motility of Fibrocytes. Conclusion The CXCR4/CXCL12 axis contributes to chemotaxis of Fibrocytes in patients in the Asthma AE group, whereas the CCR7/CCL19 axis plays an important role in patients with COA. S100A9 enhances the basal migratory motility of Fibrocytes from patients in the Asthma AE group and patients with COA.