Pathological Hyaluronan Matrices in Cystic Fibrosis Airways and Secretions

Matuska, Brittany; Comhair, Suzy; Farver, Carol; Chmiel, James F.; Midura, Ronald J.; Bonfield, Tracey L.; Lauer, Mark E.

doi:10.1165/rcmb.2015-0358oc

Cited by 24 publications

(26 citation statements)

References 34 publications

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“…HC-modified HA is prominently featured in the extracellular matrix of chronic lung diseases such as pulmonary arterial hypertension [ 11 ], asthma [ 12 ], cystic fibrosis [ 13 ], and idiopathic pulmonary fibrosis [ 14 ], that share lung inflammation in their pathogenesis, suggesting that HC-HA formation is important in either promoting the onset or delaying the resolution of lung inflammation. We therefore used self-resolving models of ALI that were induced by intratracheal instillation of LPS or gram negative bacteria Pseudomonas aeruginosa (PA) to study the kinetics and role of HC-modified HA in acute lung inflammation.…”

Section: Introductionmentioning

confidence: 99%

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

Gill

Tseng

et al. 2018

Respir Res

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BackgroundSeveral inflammatory lung diseases display abundant presence of hyaluronic acid (HA) bound to heavy chains (HC) of serum protein inter-alpha-inhibitor (IαI) in the extracellular matrix. The HC-HA modification is critical to neutrophil sequestration in liver sinusoids and to survival during experimental lipopolysaccharide (LPS)-induced sepsis. Therefore, the covalent HC-HA binding, which is exclusively mediated by tumor necrosis factor α (TNFα)-stimulated-gene-6 (TSG-6), may play an important role in the onset or the resolution of lung inflammation in acute lung injury (ALI) induced by respiratory infection.MethodsReversible ALI was induced by a single intratracheal instillation of LPS or Pseudomonas aeruginosa in mice and outcomes were studied for up to six days. We measured in the lung or the bronchoalveolar fluid HC-HA formation, HA immunostaining localization and roughness, HA fragment abundance, and markers of lung inflammation and lung injury. We also assessed TSG-6 secretion by TNFα- or LPS-stimulated human alveolar macrophages, lung fibroblast Wi38, and bronchial epithelial BEAS-2B cells.ResultsExtensive HC-modification of lung HA, localized predominantly in the peri-broncho-vascular extracellular matrix, was notable early during the onset of inflammation and was markedly decreased during its resolution. Whereas human alveolar macrophages secreted functional TSG-6 following both TNFα and LPS stimulation, fibroblasts and bronchial epithelial cells responded to only TNFα. Compared to wild type, TSG-6-KO mice, which lacked HC-modified HA, exhibited modest increases in inflammatory cells in the lung, but no significant differences in markers of lung inflammation or injury, including histopathological lung injury scores.ConclusionsRespiratory infection induces rapid HC modification of HA followed by fragmentation and clearance, with kinetics that parallel the onset and resolution phase of ALI, respectively. Alveolar macrophages may be an important source of pulmonary TSG-6 required for HA remodeling. The formation of HC-modified HA had a minor role in the onset, severity, or resolution of experimental reversible ALI induced by respiratory infection with gram-negative bacteria.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0812-1) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

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

Gill

Tseng

et al. 2018

Respir Res

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“…There are several methods to monitor shifts in hyaluronan in tissue. FACE technology is useful in complex tissues since it allows for semi-quantification of total HA, as well as the strunctural identiy of the HA regarding the change in TSG-6 mediated glycosylation and HA converting from low molecular weight to high molecular forms which are pathogenic [ 29 , 30 ]. HSAE technology, however, is able to qualitatively detect differences in size to distinguish high molecular weight vs. low molecular weight hyaluronan.…”

Section: Resultsmentioning

confidence: 99%

“…To determine the state and quantity of HA, lung homogenates were processed using FACE [ 29 ]. The process involves isolating and breaking down the HA into its component disaccharides which are fluorescently labeled and then processed with gel electrophoresis and digital imaging.…”

Section: Methodsmentioning

confidence: 99%

Chronic asthma and Mesenchymal stem cells: Hyaluronan and airway remodeling

et al. 2017

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BackgroundPrevious studies have demonstrated that ovalbumin sensitization promotes chronic asthma phenotype in murine asthma model. Human mesenchymal stem cells (hMSCs) are multipotent cells in vitro that have been shown to decrease inflammation and can reverse airway remodeling when infused into an in vivo chronic asthma model. However, the mechanism by which hMSCs reverse remodeling is still unclear. In this study, we hypothesized that hMSCs influence remodeling by decreasing extracellular matrix (ECM) deposition, more specifically by decreasing collagen I, collagen III, and hyaluronan synthesis.MethodsChronic asthma phenotype was produced in an in vitro model with 3 T3 murine airway fibroblast cells by stimulating with GM-CSF. Collagen I and collagen III gene expression was investigated using RT-PCR and Taqman techniques. Hyaluronan was evaluated using FACE and Western Blots. The chronic asthma phenotype was produced in vivo in murine model using sensitization with ovalbumin with and without hMSC infusion therapy. ECM deposition (specifically trichrome staining, soluble and insoluble collagen deposition, and hyaluronan production) was evaluated. Image quantification was used to monitor trichrome staining changes.ResultsGM-CSF which induced collagen I and collagen III production was down-regulated with hMSC using co-culture. In the in vivo model, Ovalbumin induced enhanced ECM deposition, soluble and insoluble collagen production, and lung elastance. hMSC infusions decreased ECM deposition as evidenced by decreases in soluble and insoluble collagen production.ConclusionhMSCs participate in improved outcomes of remodeling by reversing excess collagen deposition and changing hyaluronan levels.

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“…The formation of extracellular or cell surface ITIH-HA complexes promotes the adhesion of leukocytes [ 60 ]. It could be ascertained that expression of ITIH-5 within cerebral endothelium could promote the adhesion and extravasation of circulating leukocytes through the damaged cerebral vasculature, suggesting a potential detrimental role [ 20 , 63 ]. Yet, treatment with human ITI for inflammatory syndromes such as endotoxin shock has been shown to confer therapeutic effects, indicating its potential anti-inflammatory roles [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Endothelial Progenitor Cells Modulate Inflammation-Associated Stroke Vasculome

Acosta

Lee

Nguyen

et al. 2019

Stem Cell Rev and Rep

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Stroke remains a major unmet clinical need that warrants novel therapies. Following an ischemic insult, the cerebral vasculature secretes inflammatory molecules, creating the stroke vasculome profile. The present study evaluated the therapeutic effects of endothelial cells on the inflammation-associated stroke vasculome. qRT-PCR analysis revealed that specific inflammation-related vasculome genes BRM, IκB, Foxf1, and ITIH-5 significantly upregulated by oxygen glucose deprivation (OGD. Interestingly, co-culture of human endothelial cells (HEN6) with human endothelial cells (EPCs) during OGD significantly blocked the elevations of BRM, IκB, and Foxf1, but not ITIH-5. Next, employing the knockdown/antisense technology, silencing the inflammation-associated stroke vasculome gene, IκB, as opposed to scrambled knockdown, blocked the EPC-mediated protection of HEN6 against OGD. In vivo, stroke animals transplanted with intracerebral human EPCs (300,000 cells) into the striatum and cortex 4 h post ischemic stroke displayed significant behavioral recovery up to 30 days post-transplantation compared to vehicle-treated stroke animals. At 7 days post-transplantation, quantification of the fluorescent staining intensity in the cortex and striatum revealed significant upregulation of the endothelial marker RECA1 and a downregulation of the stroke-associated vasculome BRM, IKB, Foxf1, ITIH-5 and PMCA2 in the ipsilateral side of cortex and striatum of EPC-transplanted stroke animals relative to vehicle-treated stroke animals. Altogether, these results demonstrate that EPCs exert therapeutic effects in experimental stroke possibly by modulating the inflammation-plagued vasculome.

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Pathological Hyaluronan Matrices in Cystic Fibrosis Airways and Secretions

Cited by 24 publications

References 34 publications

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

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

Chronic asthma and Mesenchymal stem cells: Hyaluronan and airway remodeling

Endothelial Progenitor Cells Modulate Inflammation-Associated Stroke Vasculome

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