Deficiency in the Serum-Derived Hyaluronan-Associated Protein-Hyaluronan Complex Enhances Airway Hyperresponsiveness in a Murine Model of Asthma

Zhu, Long; Zhuo, Lisheng; Kimata, Koji; Yamaguchi, Etsuro; Watanabe, Hideto; Aronica, Mark A.; Hascall, Vincent C.; Baba, Kenji

doi:10.1159/000314362

Cited by 22 publications

(17 citation statements)

References 86 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, SHAP-HA-deficient (bikunin knock-out) mice show higher airway hyper-responsiveness to inhaled methacholine and higher late phase response to exposed aerosol ovalbumin, exhibiting an increased number of macrophages and neutrophils but decreased soluble tumor necrosis factor receptor-1 in their bronchoalveolar lavage fluid. This finding suggests that SHAP-HA has an inhibitory role in the development of airway hyper-responsiveness and allergic airway inflammation (66). Although both SHAP-HA and HC-HA purified from human AM are similar complexes, characterized by high molecular mass HA covalently linked to HC (42,43,64), there are important differences.…”

Section: Discussionmentioning

confidence: 97%

Immobilized Heavy Chain-Hyaluronic Acid Polarizes Lipopolysaccharide-activated Macrophages toward M2 Phenotype

He¹,

Zhang²,

Tighe³

et al. 2013

Journal of Biological Chemistry

117

118

View full text Add to dashboard Cite

Background: HC-HA is a unique anti-inflammatory matrix different from hyaluronic acid (HA). Results: Soluble HC-HA induces apoptosis of inflammatory neutrophils and macrophages, and immobilized HC-HA promotes M2 polarization upon LPS/TLR ligation while both enhancing macrophage phagocytosis. Conclusion: HC-HA exerts its anti-inflammatory action using multiple mechanisms. Significance: HC-HA is the first known matrix component to polarize M2b.Despite the known anti-inflammatory effect of amniotic membrane, its action mechanism remains largely unknown. HC-HA complex (HC-HA) purified from human amniotic membrane consists of high molecular weight hyaluronic acid (HA) covalently linked to the heavy chain (HC) 1 of inter-␣-trypsin inhibitor. In this study, we show that soluble HC-HA also contained pentraxin 3 and induced the apoptosis of both formyl-Met-Leu-Phe or LPS-activated neutrophils and LPS-activated macrophages while not affecting the resting cells. This enhanced apoptosis was caused by the inhibition of cell adhesion, spreading, and proliferation caused by HC-HA binding of LPS-activated macrophages and preventing adhesion to the plastic surface. Preferentially, soluble HC-HA promoted phagocytosis of apoptotic neutrophils in resting macrophages, whereas immobilized HC-HA promoted phagocytosis in LPSactivated macrophages. Upon concomitant LPS stimulation, immobilized HC-HA but not HA polarized macrophages toward the M2 phenotype by down-regulating IRF5 protein and preventing its nuclear localization and by down-regulating IL-12, TNF-␣, and NO synthase 2. Additionally, IL-10, TGF-␤1, peroxisome proliferator-activated receptor ␥, LIGHT (TNF superfamily 14), and sphingosine kinase-1 were up-regulated, and such M2 polarization was dependent on TLR ligation. Collectively, these data suggest that HC-HA is a unique matrix component different from HA and uses multiple mechanisms to suppress M1 while promoting M2 phenotype. This anti-inflammatory action of HC-HA is highly desirable to promote wound healing in diseases heightened by unsuccessful transition from M1 to M2 phenotypes.Inflammation serves as the first host response to real or perceived threats to tissue homeostasis. It is heralded by the recruitment of neutrophils, which eliminate pathogens and damaged tissues before eventually undergoing apoptosis (1-3). These apoptotic neutrophils are then removed by macrophages via phagocytosis, resulting in the restoration and maintenance of anti-inflammatory and tolerogenic milieu (4). On the contrary, delayed neutrophil apoptosis and/or impaired phagocytic clearance of apoptotic neutrophils by macrophages leads to prolonged inflammation that is the hallmark of a number of diseases (5-8). Hence, facilitation of neutrophil apoptosis and phagocytic clearance of apoptotic neutrophils by macrophages is an important strategy to limit inflammation-mediated tissue damage to restore tissue homeostasis (9 -11).Macrophages undergo phenotypic changes to adapt to the transition from proinflammatory to anti-inflammatory states of wou...

show abstract

Section: Discussionmentioning

confidence: 97%

Immobilized Heavy Chain-Hyaluronic Acid Polarizes Lipopolysaccharide-activated Macrophages toward M2 Phenotype

He¹,

Zhang²,

Tighe³

et al. 2013

Journal of Biological Chemistry

117

118

View full text Add to dashboard Cite

show abstract

“…The trypsin solution and combined washes were designated as “pericellular.” After cell counting, the cells were placed in Proteinase K solution (0.15 M Tris–HCl, pH 7.5, 0.15 M NaCl, 0.01 M CaCl 2 and 5 mM deferoxamine mesylate containing 20 U of proteinase K) and incubated for 2 hr at 55°C, and this solution was designated as “intracellular.” All samples were heated at 100°C for 15 min to inactivate protease activity and centrifuged at 15,000 g for 30 min at 4°C, after which the supernatants were analyzed. The HA concentrations were measured using the HA binding assay, as described previously . Briefly, each well in a Maxisorp microtiter plate (Nunc, Roskilde, Denmark) was coated with 50 μl of HABP (Seikagaku, Tokyo, Japan; 0.4 μg/ml in 0.1 M NaHCO 3 , pH9.2), overnight at 4°C, and subjected to blocking with 200 μl each of 2% BSA in phosphate‐buffered saline with 0.1% (v/v) Tween 20 (PBS‐T) at room temperature for 2 hr.…”

Section: Methodsmentioning

confidence: 99%

Antitumor effects of 4‐methylumbelliferone, a hyaluronan synthesis inhibitor, on malignant peripheral nerve sheath tumor

Ikuta

Ota

Zhuo

et al. 2016

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Hyaluronan (HA) has been shown to play important roles in the growth, invasion and metastasis of malignant tumors. Our previous study showing that high HA expression in malignant peripheral nerve sheath tumors (MPNST) is predictive of poor patient prognosis, prompted us to speculate that inhibition of HA synthesis in MPNST might suppress the tumorigenicity. The aim of our study was to investigate the antitumor effects of 4-methylumbelliferone (MU), an HA synthesis inhibitor, on human MPNST cells and tissues. The effects of MU on HA accumulation and tumorigenicity in MPNST cells were analyzed in the presence or absence of MU in an in vitro as well as in vivo xenograft model using human MPNST cell lines, sNF96.2 (primary recurrent) and sNF02.2 (metastatic). MU significantly inhibited cell proliferation, migration and invasion in both MPNST cell lines. HA binding protein (HABP) staining, particle exclusion assay and quantification of HA revealed that MU significantly decreased HA accumulation in the cytoplasms and pericellular matrices in both MPNST cell lines. The expression levels of HA synthase2 (HAS2) and HA synthase3 (HAS3) mRNA were downregulated after treatment with MU. MU induced apoptosis of sNF96.2 cells, but not sNF02.2 cells. MU administration significantly inhibited the tumor growth of sNF96.2 cells in the mouse xenograft model. To the best of our knowledge, our study demonstrates for the first time the antitumor effects of MU on human MPNST mediated by inhibition of HA synthesis. Our results suggest that MU may be a promising agent with novel antitumor mechanisms for MPNST.

show abstract

“…As a nonarthritis control, blood was collected from normal nonimmunized mice (n = 10). The concentration of HA in serum was determined using an HA binding assay, as described previously (15).…”

Section: Methodsmentioning

confidence: 99%

Suppression of Hyaluronan Synthesis Alleviates Inflammatory Responses in Murine Arthritis and in Human Rheumatoid Synovial Fibroblasts

Yoshioka¹,

Kozawa²,

Urakawa³

et al. 2013

Arthritis & Rheumatism

Self Cite

View full text Add to dashboard Cite

Objective. To clarify the roles of hyaluronan (HA) in joint inflammation and the process of joint destruction, using 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, in a mouse model of collagen-induced arthritis (CIA) and in a monolayer culture of fibroblastlike synoviocytes (FLS) derived from patients with rheumatoid arthritis.Methods. DAB/1J mice were immunized with type II collagen. The effects of 4-MU were evaluated by the physiologic arthritis score, paw swelling, the histologic arthritis score, and expression of matrix metalloproteinase 3 (MMP-3) and MMP-13 in chondrocytes and synovial tissue. In vitro, the effect of 4-MU on messenger RNA and protein expression of MMP-1 and MMP-3 was determined. The effects of 4-MU on HA deposition and on serum/medium concentrations of HA were analyzed using biotinylated HA binding protein staining and an HA binding assay, respectively.Results. Treatment with 4-MU in mice with CIA dramatically decreased the severity of arthritis (based on the arthritis score), paw thickness, and histopathologic changes. MMP-3 and MMP-13 expression in chondrocytes and synovial cells was significantly inhibited by 4-MU in vivo. Treatment with 4-MU also inhibited MMP-1 and MMP-3 expression in tumor necrosis factor ␣-stimulated FLS, in a dose-dependent manner. The 4-MU-induced decreases in the serum HA concentration in mice with CIA and in "medium" and "pericellular" HA concentrations in cultured FLS support the contention that the inhibitory mechanism of 4-MU is mediated by HA suppression.Conclusion. Reduced disease activity induced by 4-MU in mice with CIA revealed HA to be a crucial regulator in the course of arthritis. Therefore, 4-MU is a potential therapeutic agent in arthritis, and its inhibitory mechanism is possibly mediated by suppression of HA synthesis.

show abstract

Deficiency in the Serum-Derived Hyaluronan-Associated Protein-Hyaluronan Complex Enhances Airway Hyperresponsiveness in a Murine Model of Asthma

Cited by 22 publications

References 86 publications

Immobilized Heavy Chain-Hyaluronic Acid Polarizes Lipopolysaccharide-activated Macrophages toward M2 Phenotype

Immobilized Heavy Chain-Hyaluronic Acid Polarizes Lipopolysaccharide-activated Macrophages toward M2 Phenotype

Antitumor effects of 4‐methylumbelliferone, a hyaluronan synthesis inhibitor, on malignant peripheral nerve sheath tumor

Suppression of Hyaluronan Synthesis Alleviates Inflammatory Responses in Murine Arthritis and in Human Rheumatoid Synovial Fibroblasts

Contact Info

Product

Resources

About