Hyaluronan Fragments/CD44 Mediate Oxidative Stress–Induced MUC5B Up-Regulation in Airway Epithelium

Casalino‐Matsuda, S. Marina; Monzón, Maria E.; Day, Anthony J.; Forteza, Rosanna

doi:10.1165/rcmb.2008-0073oc

Cited by 74 publications

(68 citation statements)

References 63 publications

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“…We have previously reported that ROS induce HA fragmentation (21,23), and that Hyal1, 2, and 3 are expressed in the airway epithelium (26). We and others (26,47) have shown that Hyal2 is selectively increased in inflammatory conditions and that TNF-␣ and IL-1␤ induce Hyal2 gene and protein expression in NHBE cells (26).…”

Section: Discussionmentioning

confidence: 89%

“…For instance, GPI-anchored Hyal2 is likely involved in normal HA turnover, where Hyal2 depolymerize HA into ϳ20 kDa (ϳ50 disaccharides units) fragments, delivering them for further lysosomal degradation by Hyal1 (39,50). Soluble Hyal2 could be specifically released by GPI-PLD during inflammation, generating excess HA fragments that overwhelm HA catabolic rates, resulting in the triggering of RHAMM-and CD44-mediated intracellular signaling (22,23). It is reasonable to argue then, that GPI-Hyal2 serves constitutive physiological functions, (39,57,58), while the soluble form actively participates in host defense (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…Tissue kallikrein (TK), a serine protease involved in airway inflammation and mucus hypersecretion (15,21) is bound to, and inhibited by HMWHA at the airway epithelial surface. Exposure to reactive oxygen species (ROS) depolymerizes HA resulting in the release of active TK (15,21) and HA fragments that stimulate ciliary beating (22) and induce MUC5B up-regulation (23). Thus, fragmentation of HA at the epithelial surface can profoundly affect cell responses.…”

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confidence: 99%

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Reactive Oxygen Species and Hyaluronidase 2 Regulate Airway Epithelial Hyaluronan Fragmentation

Monzón

Fregien

Schmid

et al. 2010

Journal of Biological Chemistry

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100

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Hyaluronidase 2 (Hyal2) is a hyaluronan (HA)-degrading enzyme found intracellularly or/and anchored to the plasma membrane through glycosylphosphatidylinositol (GPI). Normal human bronchial epithelial cells (NHBE) grown at the air-liquid interphase (ALI), treated with PI-specific phospholipase C (PI-PLC), exhibited increased Hyal activity in secretions and decreased protein and activity on the apical membrane, confirming that GPI-anchored Hyal2 is expressed in NHBE cells and it remains active in its soluble form. We have reported that HA degradation was mediated by reactive oxygen species (ROS) in human airways. Here we show that ROS increase Hyal2 expression and activity in NHBE cells and that the p38MAPK signaling pathway is involved in this effect. Hyal2 induction was confirmed by using small interfering RNA (siRNA) expressing lentivirus. These in vitro findings correlated in vivo with smokers, where increased Hyal2 immunoreactivity in the epithelium was associated with augmented levels of HA and the appearance of low molecular mass HA species in bronchial secretions. In summary, this work provides evidence that ROS induce Hyal2, suggesting that Hyal2 is likely responsible for the sustained HA fragmentation in the airway lumen observed in inflammatory conditions associated with oxidative stress. Hyaluronan (HA)3 is a non-sulfated glycosaminoglycan found in the extracellular matrix, in body fluids, and in secretions of mammals. HA is synthesized by three transmembrane isoenzymes: HAS1, HAS2, and HAS3 at the inner face of the plasma membrane and translocated into the extracellular space (1).The association with various binding proteins (2, 3) confers HA with a unique plasticity to organize extracellular matrix (ECM) in a tissue specific fashion (for review see Ref. 4), varying from a tightly cross-linked mesh in cartilage to a highly hydrated matrix in dermis and vitreous humor (5).In addition, HA induces intracellular signaling by binding specific receptors at the cell surface, (6, 7) orchestrating a variety of host responses generally requiring an extensive deposition of a HA in the ECM. This deposition is essential for cumulus oophorus fertilization (8) as well as for proliferation and migration of mesenchymal cells. Airway smooth muscle cells exposed to polyinosinic acid-polycytidylic acid synthesize an abnormal HA matrix with cable-like structures that bind and retains leukocytes (9, 10), suggesting that HA play key roles on host defense against infections as well.Biological functions of HA are associated with its size (6, 11). For instance, high molecular weight HA (HMWHA) exhibit anti-angiogenic, anti-inflammatory, and immunosuppressive effects while small HA fragments are angiogenic and proinflammatory (12, 13). The contrasting responses elicited by different sizes of HA are exemplified in a recent report in which HMWHA attenuated while low molecular weight HA (LMWHA) increased ozone-induced airway hyperreactivity, in a mouse model of asthma (14).In human airway epithelium, HA is present at the lumen as...

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Reactive Oxygen Species and Hyaluronidase 2 Regulate Airway Epithelial Hyaluronan Fragmentation

Monzón

Fregien

Schmid

et al. 2010

Journal of Biological Chemistry

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100

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“…8 Furthermore, MUC5AC þ GCH induced by IL-13 in normal HBEC depends on activation of IL-13R-JAK-STAT6 and EGFR-MAPK signaling pathways, as well as NF-kB, 15 relevant in allergic asthma as IL-13 is related to the pathogenesis of this disease. 16 The regulation of MUC5B is less known, but studies using HBEC from smokers and healthy controls showed upregulation induced by oxidative stress from cigarette smoke and reactive oxygen species, 3,17 relevant agents in the etiology of COPD.…”

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confidence: 99%

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Silva

Berčík

2012

Laboratory Investigation

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Airway goblet cell hyperplasia (GCH)-detectable by mucin staining-and abnormal macrophage infiltrate are pathological features present in many chronic respiratory disorders. However, it is unknown if both factors are associated. Using in-vivo and in-vitro models, we investigated whether macrophages are related with GCH and changes in mucin immunophenotypes. Lung sections from Sprague-Dawley rats treated for 48 h with one intra-tracheal dose of PBS or LPS (n ¼ 4-6 per group) were immunophenotyped for rat-goblet cells, immune, and proliferation markers. Human monocytederived macrophages (MDM) were pre-treated with or without LPS, immunophenotyped, and their supernatant, as well as cytokines at levels equivalent to supernatant were used to challenge primary culture of normal human bronchus epithelial cells (HBEC) in air-liquid interface, followed by MUC5B and MUC5AC mucin immunostaining. An association between increased bronchiolar goblet cells and terminal-bronchiolar proliferative epithelial cells confirmed the presence of GCH in our LPS rat model, which was related with augmented bronchiolar CD68 macrophage infiltration. The in-vitro experiments have shown that MUC5AC phenotype was inhibited when HBEC were challenged with supernatant from MDM pre-treated with or without LPS. In contrast, TNF-a and interleukin-1b at levels equivalent to supernatant from LPS-treated MDM increased MUC5AC. MUC5B was induced by LPS, supernatant from LPS-treated MDM, a mix of cytokines including TNF-a and TNF-a alone at levels present in supernatant from LPS-treated MDM. We demonstrated that macrophages are related with bronchiolar GCH, and that they induced MUC5B and inhibited MUC5AC in HBEC, suggesting a role for them in the pathogenesis of airway MUC5B-related GCH. KEYWORDS: airways; cytokines; LPS; lung inflammation; TNF-alphaMucus is a gel that covers the airway epithelium and is constituted by different glycoproteins called mucins, which are secreted by goblet cells from submucosal glands and the airway epithelium. 1 Mucus dissolves noxious gases and entraps foreign particles and pathogens, facilitating their clearance by mucociliary transport as a mechanism of innate defense. 2 However, in chronic inflammatory respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), there is a pathological goblet cell hyperplasia (GCH) and mucus hypersecretion that can generate airway occlusion, associated with morbidity and death. 1 The main gel-forming mucins found in human airways are MUC5B and MUC5AC. 1 In healthy individuals, low levels of MUC5B and MUC5AC can be detected in mucus; although MUC5B is mainly present in the submucosal glands and MUC5AC is predominantly distributed in the airway epithelium. 3 In baseline conditions of chronic inflammatory respiratory disorders, MUC5B and/or MUC5AC are increased in different compartments of the respiratory tract. [3][4][5][6] For example, MUC5B and MUC5AC are augmented in small airway lumen and epithelium from patients with advanced CF; 4 GC...

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“…At least 12 mucins are detected in human lungs, of these MUC5AC and MUC5B are the predominant mucins in normal airways . Airways infection with virus or bacteria, exposure to toxic agents such as cigarette smoke and pollutants that induce airway inflammation and oxidative stress have been shown to upregulate expression of MUC5AC and MUC5B (Borchers et al, 1999;Casalino-Matsuda et al, 2009;Dohrman et al, 1998;Gensch et al, 2004;Haswell et al, 2010;Shao et al, 2004). Cigarette smoke induces expression of number of inflammatory mediators including IL-1 , IL-8, TNF-, MCP-1, leukotrienes through oxidative stress-related pathways from airway epithelial cells, resident macrophages and infiltrated neutrophils, which can increase mucus secretion (Adcock et al, 2011;Choi et al, 2010;Cohen et al, 2009;Mebratu et al, 2011).…”

Section: Mucociliary Clearancementioning

confidence: 99%

Innate Immunity of Airway Epithelium and COPD

Ganesan¹,

Sajjan²

2012

Emphysema

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Hyaluronan Fragments/CD44 Mediate Oxidative Stress–Induced MUC5B Up-Regulation in Airway Epithelium

Cited by 74 publications

References 63 publications

Reactive Oxygen Species and Hyaluronidase 2 Regulate Airway Epithelial Hyaluronan Fragmentation

Reactive Oxygen Species and Hyaluronidase 2 Regulate Airway Epithelial Hyaluronan Fragmentation

Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells

Innate Immunity of Airway Epithelium and COPD

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