Cysteine proteinases and cystatin C in bronchoalveolar lavage fluid from subjects with subclinical emphysema

Takeyabu, Kimihiro; Betsuyaku, Tomoko; Nishimura, Masaharu; Yoshioka, Atsushi; Tanino, Mishie; Miyamoto, Kenji; Kawakami, Yoshikazu

doi:10.1183/09031936.98.12051033

Cited by 72 publications

(47 citation statements)

References 29 publications

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“…Active smokers with emphysema had significantly higher CysC levels. Takeyabu et al 25 reported that increased levels of CysC were present in the bronchoalveolar lavage fluid from subjects with subclinical emphysema. Pérez-Calvo et al 15 analyzed CysC levels at the time of admission in 107 subjects with exacerbation of chronic lung disease.…”

Section: Discussionmentioning

confidence: 99%

Cystatin C as a Predictor of In-Hospital Mortality After Exacerbation of COPD

Zhou

et al. 2016

Respir Care

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BACKGROUND: COPD is associated with cardiovascular and renal dysfunction. Cystatin C (CysC) is a biomarker of renal function and an independent risk factor for all-cause and cardiovascular mortality among elderly persons. The aim of the study was to examine the prognostic role of CysC for in-hospital mortality in subjects with a COPD exacerbation. METHODS: Upon admission, serum CysC levels and arterial blood gas analysis from 477 subjects with a COPD exacerbation were measured. Clinical characteristics were also recorded. A receiver operating characteristic curve analysis was used to determine the level of CysC that discriminated survivors from nonsurvivors. Univariate and multiple logistic regression analyses were used to identify the risk factors for in-hospital mortality. To reduce the influence of confounders, subgroup analyses were performed according to the comorbidities, including states of heart failure, renal dysfunction, and pH, P aCO 2 , and P aO 2 levels. RESULTS: During the in-hospital period, 59 subjects died, and 418 subjects recovered. The decedent group showed lower pH (7.27 ؎ 0.17 vs 7.38 ؎ 0.06, P < .001), higher CysC (2.21 ؎ 1.05 mg/L vs 1.39 ؎ 0.54 mg/L, P < .001), higher P aCO 2 (77 ؎ 39 mm Hg vs 48 ؎ 14 mm Hg, P < .001), and lower P aO 2 (74 ؎ 32 mm Hg vs 84 ؎ 26 mm Hg, P < .001) levels. The area under the receiver operating characteristic curve for the CysC prediction of death was 0.77 (95% CI 0.70 -0.84). CysC values >1.59 mg/L were associated with significantly higher inhospital mortality (relative risk ‫؍‬ 5.49, 95% CI 3.24 -9.32, P < .001). Multiple logistic regression analysis showed that pH <7.20, CysC >1.59 mg/L, and heart failure were independent predictors of in-hospital mortality. The subgroup analysis showed that the comorbid states of renal dysfunction, congestive heart failure, and the levels of pH, P aCO 2 , and P aO 2 did not alter the conclusion that CysC was a mortality risk factor for subjects with a COPD exacerbation. CONCLUSION: CysC was a strong and independent risk factor for hospital mortality secondary to COPD exacerbation.

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Section: Discussionmentioning

confidence: 99%

Cystatin C as a Predictor of In-Hospital Mortality After Exacerbation of COPD

Zhou

et al. 2016

Respir Care

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“…In terms of alveolar remodeling, asthma is generally considered a disease with normal alveoli; in contrast, alveolar destruction with secondary alveolar enlargement is a characteristic feature of emphysema (Elias, 2004). Studies of emphysematous human tissues have highlighted alterations that heighten tissue proteolysis, such as increased elastin degradation and enhanced expression of proteases (Ohnishi et al, 1998;Takeyabu et al, 1998). However, these changes have also been documented in severe asthma patients, leading to COPD-like alterations in lung compliance (Bousquet et al, 1996;Gelb and Zamel, 2000).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of basic fibroblast growth factor in the development of emphysema induced by interferon-γ

et al. 2011

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Recent clinical evidence indicates that the non-eosinophilic subtype of severe asthma is characterized by fixed airway obstruction, which may be related to emphysema. Transgenic studies have demonstrated that high levels of IFN-γ in the airways induce emphysema. Fibroblast growth factor 2 (FGF2), which is the downstream mediator of TGF-β, is important in wound healing. We investigated the role of FGF2 in IFN-γ-induced emphysema and the therapeutic effects of recombinant FGF2 in the prevention of emphysema in a severe non-eosinophilic asthma model. To evaluate the role of FGF2 in IFN-γ-induced emphysema, lung targeted IFN-γ transgenic mice were cross-bred with FGF2-deficient mice. A severe non-eosinophilic asthma model was generated by airway application of LPS-containing allergens twice a week for 4 weeks. To evaluate protective effects of FGF2, recombinant FGF2 (10 μ g) was injected subcutaneously during allergen challenge in the severe asthma model. We found that non-eosinophilic inflammation and emphysema induced by transgenic overexpression of IFN-γ in the airways were aggravated by the absence of FGF2. Airway challenge with LPS-containing allergens induced more inflammation in mice sensitized with LPS-containing allergens compared to challenge with allergens alone. In addition, LPS-induced lung inflammation and emphysema depended on IFN-γ but not on IL-13. Interestingly, emphysema in the severe asthma model was significantly inhibited by treatment with recombinant FGF2 during allergen challenge, whereas lung inflammation was unaffected. Therefore, our present data suggest that FGF2 may help protect against IFN-γ-induced emphysema, and that recombinant FGF2 may help lessen the severity of emphysema.

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“…The presence of secreted cathepsins in the lung may be necessary to regulate the activities of inducible microbicidal proteins and peptides. A naturally occurring inhibitor of cathepsins, cystatin C, has been detected in the BAL of smokers (36). Interestingly, increased levels of cathepsin L and cystatin C were observed in the BAL of smokers with emphysema compared with smokers without emphysema (36); however, the mere presence of active cathepsin L suggests that cystatin C levels were not sufficient to inhibit cathepsin L activity in smokers BAL.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Human β-Defensins 2 and 3 by Elastolytic Cathepsins

Taggart

Greene

Smith

et al. 2003

The Journal of Immunology

195

128

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β-Defensins are antimicrobial peptides that contribute to the innate immune responses of eukaryotes. At least three defensins, human β-defensins 1, 2, and 3 (HBD-1, -2, and -3), are produced by epithelial cells lining the respiratory tract and are active toward Gram-positive (HBD-3) and Gram-negative (HBD-1, -2, and -3) bacteria. It has been postulated that the antimicrobial activity of defensins is compromised by changes in airway surface liquid composition in lungs of patients with cystic fibrosis (CF), therefore contributing to the bacterial colonization of the lung by Pseudomonas and other bacteria in CF. In this report we demonstrate that HBD-2 and HBD-3 are susceptible to degradation and inactivation by the cysteine proteases cathepsins B, L, and S. In addition, we show that all three cathepsins are present and active in CF bronchoalveolar lavage. Incubation of HBD-2 and -3 with CF bronchoalveolar lavage leads to their degradation, which can be completely (HBD-2) or partially (HBD-3) inhibited by a cathepsin inhibitor. These results suggest that β-defensins are susceptible to degradation and inactivation by host proteases, which may be important in the regulation of β-defensin activity. In chronic lung diseases associated with infection, overexpression of cathepsins may lead to increased degradation of HBD-2 and -3, thereby favoring bacterial infection and colonization.

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Cysteine proteinases and cystatin C in bronchoalveolar lavage fluid from subjects with subclinical emphysema

Cited by 72 publications

References 29 publications

Cystatin C as a Predictor of In-Hospital Mortality After Exacerbation of COPD

Cystatin C as a Predictor of In-Hospital Mortality After Exacerbation of COPD

Protective effects of basic fibroblast growth factor in the development of emphysema induced by interferon-γ

Inactivation of Human β-Defensins 2 and 3 by Elastolytic Cathepsins

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