Imbalance between Cysteine Proteases and Inhibitors in a Baboon Model of Bronchopulmonary Dysplasia

Altiok, Ozden; Yasumatsu, Ryuji; Bingol-Karakoc, Gulbin; Riese, Richard J.; Stahlman, Mildred T.; Dwyer, W. G.; Pierce, Richard A.; Brὂmme, Dieter; Weber, Ekkehard; Çataltepe, Sule

doi:10.1164/rccm.200503-425oc

Cited by 67 publications

(54 citation statements)

References 57 publications

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“…The levels of cystatin C, the major cathepsin H inhibitor [19], were two-fold higher in PAP patients compared with controls; however, the percentage of active cathepsin H increased from 3% in control subjects to 85% in PAPjuv patients. Obviously, the capacity to cope with excessive proteolytic activity in the human lung is limited, which is supported by animal data [15]. Cystatin C is synthesised by all nucleated cells [41,42].…”

Section: Discussionmentioning

confidence: 91%

“…ISHII and co-workers [11,12] identified active cathepsin H in bronchoalveolar lavage fluid (BALF) and suggested type II cells and alveolar macrophages as the main sources of the enzyme. Others have found altered amounts and activities of cathepsin H in BALF of different patient groups [13,14] and in animal models of lung diseases [15]. The amount and activity of cathepsin H in relation to its natural substrates, the hydrophobic surfactant proteins SP-B and SP-C, are unknown.…”

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confidence: 99%

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Cathepsin H and napsin A are active in the alveoli and increased in alveolar proteinosis

Woischnik¹,

Bauer²,

Aboutaam³

et al. 2008

Eur Respir J

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Pulmonary alveolar proteinosis (PAP) is a group of rare diseases with disturbed homeostasis of alveolar surfactant. While 90% of the primary adult forms are caused by granulocyte-macrophage colony-stimulating factor autoantibodies, the underlying cause of the juvenile form remains unknown. In order to distinguish primary from secondary effects in the pathogenesis of these two forms, the present authors studied the surfactant protein processing proteases napsin A and cathepsin H.In total, 16 controls, 20 patients with juvenile PAP and 13 adults with idiopathic PAP were enrolled. Amounts and activities of the proteases in the bronchoalveolar lavage fluid (BALF) were determined by immunoblotting and specific substrate cleavage.Both proteases were present and active in BALF from controls and increased in juvenile and adult PAP patients. The amount of active cathepsin H in relation to total cathepsin H was increased in PAP patients compared with controls. Cystatin C, the physiological inhibitor of cathepsin H in the alveolar space, was not increased to the same degree as cathepsin H, resulting in an imbalance of inhibitor to protease in the alveolar space.A general defect in napsin A or cathepsin H expression or activity was not the specific cause for abnormal surfactant accumulation in juvenile pulmonary alveolar proteinosis.

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

Cathepsin H and napsin A are active in the alveoli and increased in alveolar proteinosis

Woischnik¹,

Bauer²,

Aboutaam³

et al. 2008

Eur Respir J

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“…Activation of CB has been implicated in fibrosis in ILD under various stresses. 23,24 As CB has also been involved in the turnover/degradation of ECM, lysosomal cysteine proteases could also have a role in the development of lung fibrosis. 25 And fibroblasts are regarded as the major cell type that mediates the onset and progression of lung fibrosis by secreting large amounts of ECM proteins.…”

Section: Discussionmentioning

confidence: 99%

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

Zhang

et al. 2015

Laboratory Investigation

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Cathepsin B (CB) is involved in the turnover of proteins and has various roles in maintaining the normal metabolism of cells. In our recent study, CB is increased in the muscles of polymyositis/dermatomyositis (PM/DM). However, the role of CB in interstitial lung disease (ILD) has not been reported. ILD is a frequent complication of PM/DM, which is the leading cause of death in PM/DM. It carries high morbidity and mortality in connective tissue diseases, characterized by an overproduction of inflammatory cytokines and induced fibrosis, resulting in respiratory failure. The etiology and pathogenesis of ILD remain incompletely understood. This study investigated whether treatment with CA-074Me, a specific inhibitor of CB, attenuates ILD in PM. CB expression, inflammation, and fibrosis were analyzed in the lung tissues from patients with PM/DM. The animal model of PM was induced in guinea pigs with Coxsackie virus B1 (CVB1). CA-074Me was given 24 h after CVB1 injection for 7 consecutive days. At the end of the experiment, the animals were killed and lung tissues were collected for the following analysis. Inflammation, fibrosis and apoptosis cells, and cytokines were assessed by histological examinations and immunohistochemical analyses, western blot analysis and transferasemediated dUTP nick-end labeling assay. In patients with PM/DM, the protein levels of CB were significantly elevated in lung tissues compared with healthy controls, which correlated with increases in inflammation and fibrosis. Similarly, the expression of CB, inflammation and fibrosis, CD8 þ T cell, CD68 þ cell, tumor necrosis factor-alpha, transforming growth factor-beta1 infiltrations, and apoptotic cell death were significantly increased in lung tissues of the guinea-pig model of CVB1-induced PM. These changes were attenuated by the administration of CA-074Me. In conclusion, this study demonstrates that PM/DM increases CB expression in lung tissues and inhibition of CB reduces ILD in a guinea-pig model of CVB1-induced PM. This finding suggests that CB may be a potential therapeutic target for ILD.

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“…Breakdown of elastin in this disease has been attributed to inflammation linked to increased elastolytic activity in lung (8)(9)(10), resulting from infection or hyperoxia, conditions that often complicate the course of infants who are born very prematurely (11). Authentic animal models of CLD also exhibit lung inflammation and increased protease activity in response to lengthy MV-O 2 , resulting in lung growth arrest (12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Inhibiting Lung Elastase Activity Enables Lung Growth in Mechanically Ventilated Newborn Mice

Hilgendorff

Parai²,

Ertsey³

et al. 2011

Am J Respir Crit Care Med

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Rationale: Mechanical ventilation with O 2 -rich gas (MV-O 2 ) offers life-saving treatment for respiratory failure, but also promotes lung injury. We previously reported that MV-O 2 of newborn mice increased lung elastase activity, causing elastin degradation and redistribution of elastic fibers from septal tips to alveolar walls. These changes were associated with transforming growth factor (TGF)-b activation and increased apoptosis leading to defective alveolarization and lung growth arrest, as seen in neonatal chronic lung disease. Objectives: To determine if intratracheal treatment of newborn mice with the serine elastase inhibitor elafin would prevent MV-O 2 -induced lung elastin degradation and the ensuing cascade of events causing lung growth arrest. Methods: Five-day-old mice were treated via tracheotomy with recombinant human elafin or vehicle (lactated-Ringer solution), followed by MV with 40% O 2 for 8-24 hours; control animals breathed 40% O 2 without MV. At study's end, lungs were harvested to assess key variables noted below. Measurements and Main Results: MV-O 2 of vehicle-treated pups increased lung elastase and matrix metalloproteinase-9 activity when compared with unventilated control animals, causing elastin degradation (urine desmosine doubled), TGF-b activation (pSmad-2 tripled), and apoptosis (cleaved-caspase-3 increased 10-fold). Quantitative lung histology showed larger and fewer alveoli, greater inflammation, and scattered elastic fibers. Elafin blocked these MV-O 2 -induced changes. Conclusions: Intratracheal elafin, by blocking lung protease activity, prevented MV-O 2 -induced elastin degradation, TGF-b activation, apoptosis, and dispersion of matrix elastin, and attenuated lung structural abnormalities noted in vehicle-treated mice after 24 hours of MV-O 2 . These findings suggest that elastin breakdown contributes to defective lung growth in response to MV-O 2 and might be targeted therapeutically to prevent MV-O 2 -induced lung injury.

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Imbalance between Cysteine Proteases and Inhibitors in a Baboon Model of Bronchopulmonary Dysplasia

Cited by 67 publications

References 57 publications

Cathepsin H and napsin A are active in the alveoli and increased in alveolar proteinosis

Cathepsin H and napsin A are active in the alveoli and increased in alveolar proteinosis

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

Inhibiting Lung Elastase Activity Enables Lung Growth in Mechanically Ventilated Newborn Mice

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