Rapid clearance of heavy chain-modified hyaluronan during resolving acute lung injury

Ni, Kevin; Gill, Amar; Tseng, Victor; Mikosz, Andrew M.; Koike, Kengo; Beatman, Erica L.; Xu, Cassie Y.; Cao, Danting; Gally, Fabienne; Mould, Kara J.; Serban, Karina A.; Schweitzer, Kelly S.; March, Keith L.; Janssen, William J.; Nozik‐Grayck, Eva; Garantziotis, Stavros; Petrache, Irina

doi:10.1186/s12931-018-0812-1

Cited by 20 publications

(30 citation statements)

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“…Intracranial administration of oligoHA and hyaluronidase were both able to clear HC in a preterm rabbit pup model of glycerol-induced ischemic intraventricular hemorrhage 38 . In endotoxic and infectious models of acute lung injury, HC clearance coincided with induction of hyaluronidase gene expression in recruited alveolar macrophages 37 . We therefore conclude elevated hyaluronidase activity contributes to clearance of HC-HA from the lung.…”

Section: Discussionmentioning

confidence: 99%

“…Vascular HA matrices in the plexiform lesions of PH are often covalently modified by heavy chains transferred from serum antitrypsin inter-α-inhibitor (IαI) to HA in a reaction catalyzed by TNF-α stimulated gene 6 (TSG-6) 53 . The resultant HC-HA matrix imparts additional functional versatility to HA including a decisive role in leukocyte trafficking, tissue macrophage programming in the lung 37,54 , and regulation of fibroblast-to-myofibroblast differentiation 55 . Derangement of these processes are well-described in models of pulmonary hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…It is also possible that this peripheral HA breakdown could be driven by other adventitial cell types. For instance, lung interstitial macrophages are recruited to the exterior vessel wall after just 4 days of hypoxia 60 and express high levels of Hyal2 in a model of LPS-induced lung injury 37 . HYAL2 and HA fragmentation have been implicated in matrix destruction, lung inflammation, and loss of lung function associated with COPD 61 .…”

Section: Discussionmentioning

confidence: 99%

“…www.nature.com/scientificreports www.nature.com/scientificreports/ HA may undergo reorganization via covalent transfer of the heavy chain (HC) from the serum protein inter-α-inhibitor (IαI). Clearance of the HC modification is a marker of increase hyaluronidase activity and HA turnover 37,38 . To determine whether loss of SOD3 alters the heavy chain modification in hypoxia, we performed immunoblotting for detection of IαI-HC, released upon hyaluronidase digestion of HC-HA complexes present in lung lysates.…”

Section: Loss Of Sod3 Disrupts Integrity Of Lung Hyaluronan By Augmenmentioning

confidence: 99%

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Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Tseng

Allawzi

et al. 2020

Sci Rep

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chronic hypoxia leads to pathologic remodeling of the pulmonary vasculature and pulmonary hypertension (PH). The antioxidant enzyme extracellular superoxide dismutase (SOD3) protects against hypoxia-induced pH. Hyaluronan (HA), a ubiquitous glycosaminoglycan of the lung extracellular matrix, is rapidly recycled at sites of vessel injury and repair. We investigated the hypothesis that SOD3 preserves HA homeostasis by inhibiting oxidative and enzymatic hyaluronidase-mediated HA breakdown. In SOD3-deficient mice, hypoxia increased lung hyaluronidase expression and activity, hyaluronan fragmentation, and effacement of HA from the vessel wall of small pulmonary arteries. Hyaluronan fragmentation corresponded to hypoxic induction of the cell surface hyaluronidase-2 (Hyal2), which was localized in the vascular media. Human pulmonary artery smooth muscle cells (HPASMCs) demonstrated hypoxic induction of Hyal2 and SOD-suppressible hyaluronidase activity, congruent to our observations in vivo. fragmentation of homeostatic high molecular weight HA promoted HpASMc proliferation in vitro, whereas pharmacologic inhibition of hyaluronidase activity prevented hypoxia-and oxidant-induced proliferation. Hypoxia initiates SOD3-dependent alterations in the structure and regulation of hyaluronan in the pulmonary vascular extracellular matrix. these changes occurred soon after hypoxia exposure, prior to appearance of pH, and may contribute to the early pathogenesis of this disease.Pulmonary hypertension (PH) is an incurable and fatal disease characterized by intimal thickening, muscular hypertrophy, excessive matrix deposition, and stiffening of arteries in the lung. Chronic hypoxia is a major cause and consequence of PH in humans. It is the most prevalent etiology of precapillary PH in humans (WHO Group 3 disease). The onset of PH in patients with hypoxia due to intrinsic lung disease portends a grim prognosis for survival, post-transplant outcome, and quality of life 1,2 . Therefore, there is an urgent need for research on the molecular pathogenesis of hypoxic pulmonary hypertension.One facet of this disease is the presence of high oxidative stress within the vessel wall and perivascular matrix 3 . Extracellular superoxide dismutase (SOD3) is crucial for neutralization of this stress. Global knockout 4 , selective deletion from smooth muscle cells 5 , and disrupted matrix-binding single nucleotide polymorphisms 6 of SOD3 result in a great susceptibility to hypoxia-induced vascular inflammation, fibrosis, and PH. On the other hand, lung-specific overexpression of SOD3 7 , adenoviral gene transfer of human SOD3 8 , and treatment with an inorganic metalloporphyrin SOD3 mimetic 9 are protective against PH in rodent models. In the advanced stages of PH in humans, SOD3 levels are epigenetically reduced by histone deacetylation 10 .There is a critical gap in our understanding of how the extracellular oxidative environment can lead to irreversible pulmonary vascular remodeling in chronic hypoxia. Amassing evidence points to a central role f...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Loss Of Sod3 Disrupts Integrity Of Lung Hyaluronan By Augmenmentioning

confidence: 99%

See 2 more Smart Citations

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Tseng

Allawzi

et al. 2020

Sci Rep

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“…HC-modified HA (HC-HA) formation improves survival outcomes in endotoxemic sepsis [5] , [6] , associated with retention of neutrophils within liver sinusoids [7] , [8] , [9] . However, HC-HA exerted only modest effects against localized intratracheal (IT) endotoxic exposures that cause acute lung injury (ALI) [10] , despite rapid HC-modification of HA that paralleled the kinetics of lung inflammation. It remains unclear why HC-HA has a distinct impact depending on the route of lipopolysaccharide (LPS) exposure.…”

Section: Introductionmentioning

confidence: 99%

Intravascular heavy chain-modification of hyaluronan during endotoxic shock

Gill

Cao

et al. 2019

Biochemistry and Biophysics Reports

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During inflammation, the covalent linking of the ubiquitous extracellular polysaccharide hyaluronan (HA) with the heavy chains (HC) of the serum protein inter alpha inhibitor (IαI) is exclusively mediated by the enzyme tumor necrosis factor α (TNFα)-stimulated-gene-6 (TSG-6). While significant advances have been made regarding how HC-modified HA (HC-HA) is an important regulator of inflammation, it remains unclear why HC-HA plays a critical role in promoting survival in intraperitoneal lipopolysaccharide (LPS)-induced endotoxemia while exerting only a modest role in the outcomes following intratracheal exposure to LPS. To address this gap, the two models of intraperitoneal LPS-induced endotoxic shock and intratracheal LPS-induced acute lung injury were directly compared in TSG-6 knockout mice and littermate controls. HC-HA formation, endogenous TSG-6 activity, and inflammatory markers were assessed in plasma and lung tissue. TSG-6 knockout mice exhibited accelerated mortality during endotoxic shock. While both intraperitoneal and intratracheal LPS induced HC-HA formation in lung parenchyma, only systemically-induced endotoxemia increased plasma TSG-6 levels and intravascular HC-HA formation. Cultured human lung microvascular endothelial cells secreted TSG-6 in response to both TNFα and IL1β stimulation, indicating that, in addition to inflammatory cells, the endothelium may secrete TSG-6 into circulation during systemic inflammation. These data show for the first time that LPS-induced systemic inflammation is uniquely characterized by significant vascular induction of TSG-6 and HC-HA, which may contribute to improved outcomes of endotoxemia.

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Inter‐alpha‐trypsin inhibitor heavy chain 4: A serologic marker relating to disease risk, activity, and treatment outcomes of rheumatoid arthritis

2022

Clinical Laboratory Analysis

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Objective Inter‐alpha‐trypsin inhibitor heavy chain 4 (ITIH4) regulates immunity and inflammation, but its clinical role in rheumatoid arthritis (RA) patients remains unclear. Hence, this study was conducted to explore the association of circulating ITIH4 with disease risk, clinical features, inflammatory cytokines, and treatment outcomes of RA. Methods After the enrollment of 93 active RA patients and 50 health controls (HCs), their serum ITIH4 level was analyzed by enzyme‐linked immunosorbent assay (ELISA). For RA patients only, serum ITIH4 level at week (W) 6 and W12 after treatment was also analyzed. Besides, serum tumor necrosis factor‐alpha (TNF‐α), interleukin (IL)‐1β, IL‐6, and IL‐17A at baseline of RA patients were also detected by ELISA. Results ITIH4 was downregulated in RA patients (151.1 (interquartile range (IQR): 106.2–213.5) ng/mL) than in HCs (306.8 (IQR: 238.9–435.1) ng/mL) (p < 0.001). Furthermore, ITIH4 was negatively related to C‐reactive protein (CRP) (rs = −0.358, p < 0.001) and 28‐joint disease activity score using erythrocyte sedimentation rate (DAS28‐ESR) (rs = −0.253, p = 0.014) in RA patients, but not correlated with other clinical features (all p > 0.05). Besides, ITIH4 was negatively linked with TNF‐α (rs = −0.337, p = 0.001), IL‐6 (rs = −0.221, p = 0.033), and IL‐17A (rs = −0.368, p < 0.001) in RA patients, but not correlated with IL‐1β (rs = −0.195, p = 0.061). Moreover, ITIH4 was gradually elevated in RA patients from baseline to W12 after treatment (p < 0.001). Additionally, the increment of ITIH4 at W6 and W12 was linked with treatment response and remission in RA patients (all p < 0.05). Conclusion Circulating ITIH4 possesses clinical utility in monitoring disease risk, inflammation, disease activity, and treatment outcomes of RA.

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Rapid clearance of heavy chain-modified hyaluronan during resolving acute lung injury

Cited by 20 publications

References 69 publications

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Intravascular heavy chain-modification of hyaluronan during endotoxic shock

Inter‐alpha‐trypsin inhibitor heavy chain 4: A serologic marker relating to disease risk, activity, and treatment outcomes of rheumatoid arthritis

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