COPD Exacerbations Are Associated With Proinflammatory Degradation of Hyaluronic Acid

Papakonstantinou, Eleni; Roth, Michael; Klagas, Ioannis; Karakiulakis, George; Tamm, Michael; Stolz, Daiana

doi:10.1378/chest.15-0153

Cited by 34 publications

(36 citation statements)

References 42 publications

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“…Moreover, a significant turnover of hyaluronic acid was observed in BALF during exacerbations. 15 These data indicate that during AECOPD, there is an increased turnover of ECM molecules, which may be associated with airway remodeling and lung function decline during exacerbations of COPD.…”

mentioning

confidence: 75%

Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD

Stolz

Leeming

Kristensen

et al. 2017

Chest

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mentioning

confidence: 75%

Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD

Stolz

Leeming

Kristensen

et al. 2017

Chest

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“…First, exacerbations are associated with significant pulmonary inflammation including activation of matrix metalloproteinases (31) and increased hyaluronidase activity (32), which may trigger a number of permanent changes to the lung parenchyma including airway fibrosis and additional loss of alveolar tissue. Second, some subjects who suffer prolonged exacerbations may not fully recover before the next episode begins leading to a progressive deterioration with each event and faster lung function loss over time (33).…”

Section: Discussionmentioning

confidence: 99%

Acute Exacerbations and Lung Function Loss in Smokers with and without Chronic Obstructive Pulmonary Disease

Dransfield

Kunisaki

Strand

et al. 2017

Am J Respir Crit Care Med

276

219

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Rationale: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase the risk of death and drive healthcare costs, but whether they accelerate loss of lung function remains controversial. Whether exacerbations in subjects with mild COPD or similar acute respiratory events in smokers without airflow obstruction affect lung function decline is unknown.Objectives: To determine the association between acute exacerbations of COPD (and acute respiratory events in smokers without COPD) and the change in lung function over 5 years of follow-up.Methods: We examined data on the first 2,000 subjects who returned for a second COPDGene visit 5 years after enrollment. Baseline data included demographics, smoking history, and computed tomography emphysema. We defined exacerbations (and acute respiratory events in those without established COPD) as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for hospitalization. Throughout the 5-year follow-up period, we collected self-reported acute respiratory event data at 6-month intervals. We used linear mixed models to fit FEV 1 decline based on reported exacerbations or acute respiratory events. Measurements and Main Results:In subjects with COPD, exacerbations were associated with excess FEV 1 decline, with the greatest effect in Global Initiative for Chronic Obstructive Lung Disease stage 1, where each exacerbation was associated with an additional 23 ml/yr decline (95% confidence interval, 2-44; P = 0.03), and each severe exacerbation with an additional 87 ml/yr decline (95% confidence interval, 23-151; P = 0.008); statistically significant but smaller effects were observed in Global Initiative for Chronic Obstructive Lung Disease stage 2 and 3 subjects. In subjects without airflow obstruction, acute respiratory events were not associated with additional FEV 1 decline.Conclusions: Exacerbations are associated with accelerated lung function loss in subjects with established COPD, particularly those with mild disease. Trials are needed to test existing and novel therapies in subjects with early/mild COPD to potentially reduce the risk of progressing to more advanced lung disease.Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

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“…3 LMMHA is dramatically increased in patients with idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma and acute respiratory distress Abbreviations: BALF, bronchoalveolar lavage fluid; ECM, extracellular matrix; ERK 1/2, extracellular signal-regulated kinase 1/2; IFN-b, interferon-b; IL-1b, interleukin-1b; IRF-3, interferon regulatory factor 3; KC, keratinocyte cell-derived chemokine; LMMHA, low-molecular-mass hyaluronan; Mcl-1, myeloid leukaemia cell differentiation protein; MMP-9, matrix metalloproteinase-9; MPO, myeloperoxidase; PBS, phosphate-buffered saline; PI3K, phosphoinositide 3-kinase; TLR, Toll-like receptor; WT, wild-type ª 2018 John Wiley & Sons Ltd, Immunology, 155, 387-395 syndrome. [4][5][6][7] A previous study on the role of LMMHA in lung injury revealed that blocking the effect of LMMHA with specific peptides decreases neutrophil infiltration and fibrosis activity and alleviates lung tissue damage in a bleomycin-mediated LMMHA-induced mouse lung injury model. 8 These studies establish the importance of LMMHA in respiratory disorders and encourage further study of the pro-inflammatory properties of LMMHA.…”

Section: Introductionmentioning

confidence: 99%

Low‐molecular‐mass hyaluronan induces pulmonary inflammation by up‐regulation of Mcl‐1 to inhibit neutrophil apoptosis via PI3K/Akt1 pathway

Zhao

Zhang

2018

Immunology

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Although low-molecular-mass hyaluronan (LMMHA) has been implicated in pulmonary inflammatory diseases, the signalling pathway of LMMHA (200 000 molecular weight) that initiates the inflammatory response in lung is still unknown. In this study, we evaluate the role of phosphoinositide 3-kinase (PI3K) and its downstream signalling pathway in LMMHA-induced lung inflammatory responses. Our results indicate that pharmacological inhibition of PI3K or genetic deletion of Akt1 enhances neutrophil apoptosis, attenuates neutrophil influx into the lungs of mice and diminishes the expression of pro-inflammatory factors such as interleukin-6, keratinocyte cell-derived chemokine and pro-matrix metalloproteinase-9 in bronchoalveolar lavage fluid after intratracheal administration of LMMHA. More importantly, we found that PI3K/Akt1 participates in LMMHA-induced inflammatory responses, which are mainly mediated by the myeloid leukaemia cell differentiation protein (Mcl-1). Our study suggests that LMMHA induced significantly increased levels of inflammatory factors in bronchoalveolar lavage fluid and activation of the PI3K/Akt1 pathway, which up-regulates the expression of the anti-apoptotic protein Mcl-1 and inhibits the activation of caspase-3, thereby suppressing neutrophil apoptosis to trigger lung inflammation. These findings reveal a novel molecular mechanism underlying sterile inflammation and provides a new potential target for the treatment of pulmonary disease.

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COPD Exacerbations Are Associated With Proinflammatory Degradation of Hyaluronic Acid

Cited by 34 publications

References 42 publications

Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD

Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD

Acute Exacerbations and Lung Function Loss in Smokers with and without Chronic Obstructive Pulmonary Disease

Low‐molecular‐mass hyaluronan induces pulmonary inflammation by up‐regulation of Mcl‐1 to inhibit neutrophil apoptosis via PI3K/Akt1 pathway

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