Reduced proteolysis of surfactant protein A and changes of the bronchoalveolar lavage fluid proteome by inhaled α1-protease inhibitor in cystic fibrosis

Griese, Matthias; Bredow, Christina von; Birrer, P.

doi:10.1002/1522-2683(200101)22:1<165::aid-elps165>3.0.co;2-h

Cited by 48 publications

(35 citation statements)

References 25 publications

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“…Chronic airway inflammatory diseases, such as cystic fibrosis, have also been associated with decreased SP-A and SP-D (43), and have been found to have high numbers of airway apoptotic cells (26). Protease/ antiprotease imbalance in these diseases may also contribute to impaired collectin-mediated removal of apoptotic cells, either through direct degradation of collectins (44), or through degradation of their receptor. In this vein, we have observed that elastase cleaves calreticulin and CD91 (our unpublished observation), as well as the phosphatidylserine receptor (26).…”

Section: Discussionmentioning

confidence: 99%

Role of Surfactant Proteins A, D, and C1q in the Clearance of Apoptotic Cells In Vivo and In Vitro: Calreticulin and CD91 as a Common Collectin Receptor Complex

Vandivier¹,

Ogden

Fadok³

et al. 2002

The Journal of Immunology

478

405

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Removal of cells dying by apoptosis is essential to normal development, maintenance of tissue homeostasis, and resolution of inflammation. Surfactant protein A (SP-A) and surfactant protein D (SP-D) are high abundance pulmonary collectins recently implicated in apoptotic cell clearance in vitro. Other collectins, such as mannose-binding lectin and the collectin-like C1q, have been shown to bind to apoptotic cells and drive ingestion through interaction with calreticulin and CD91 on the phagocyte in vitro. However, only C1q has been shown to enhance apoptotic cell uptake in vivo. We sought to determine the relative importance of SP-A, SP-D, and C1q in pulmonary clearance of apoptotic cells using knockout and overexpressing mice, and to determine the role of calreticulin and CD91 in this process. SP-A, SP-D, and C1q all enhanced apoptotic cell ingestion by resident murine and human alveolar macrophages in vitro. However, only SP-D altered apoptotic cell clearance from the naive murine lung, suggesting that SP-D plays a particularly important role in vivo. Similar to C1q and mannose-binding lectin, SP-A and SP-D bound to apoptotic cells in a localized, patchy pattern and drove apoptotic cell ingestion by phagocytes through a mechanism dependent on calreticulin and CD91. These results suggest that the entire collectin family of innate immune proteins (including C1q) works through a common receptor complex to enhance removal of apoptotic cells, and that collectins are integral, organ-specific components of the clearance machinery.

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Section: Discussionmentioning

confidence: 99%

Role of Surfactant Proteins A, D, and C1q in the Clearance of Apoptotic Cells In Vivo and In Vitro: Calreticulin and CD91 as a Common Collectin Receptor Complex

Vandivier¹,

Ogden

Fadok³

et al. 2002

The Journal of Immunology

478

405

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“…The predominance of the LMW (¡20 kD) proteins in CF BALF may at least partly be due to an accumulation of degraded structure, defence, bacterial or in¯ammatory proteins. This is in accordance with the data of a previous report by the authors, where an 8 week inhalation of a 1 -PI in CF patients led to a signi®cant reduction in the number and Vol% of these LMW proteins ¡20 kD [20]. Various proteins were seen in CF, which were not present in controls and vice versa.…”

Section: Discussionmentioning

confidence: 99%

Surfactant protein A and other bronchoalveolar lavage fluid proteins are altered in cystic fibrosis

Bredow

Birrer²,

Griese³

2001

Eur Respir J

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Inflammation and proteolytic processes play an important role in the progression of cystic fibrosis (CF) lung disease. The goal of this study was to describe bronchoalveolar lavage fluid (BALF) protein pattern of CF patients in comparison to controls and to assess if there is proteolytic degradation of surfactant protein A (SP-A), an important innate host defence component of the lungs.BALFs from 17 clinically stable CF patients and from eight healthy children were separated by two-dimensional gel electrophoresis. Silver staining was used to show BALF proteins and Western blotting to detect SP-A isoforms.In CF, BALF proteins of a low molecular weight ≤20 kD were more abundant than in controls. Various proteins were seen in CF which were not present in controls andvice versa. Degradation of SP-A was present in 15 of 17 CF BALFs but in none of the controls, in contrast polymeric isoforms were seen in all controls and in four of 17 CF patients.Proteolytic damage to surfactant protein A and significant changes of normal bronchoalveolar lavage fluid proteins occur in lungs of cystic fibrosis patients. Identification of altered bronchoalveolar lavage fluid proteins may give new insights into pathogenic mechanisms and provide new targets for therapy.

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“…This study in CF patients with an FEV1 of .60% of the predicted value clearly demonstrated free HLE in the alveolar compartment, which was neutralised dose-dependently and reached free anti-HLE capacity in some cases. In another smaller study, treatment with a 1 -AT in the lower dose range led to reduced levels of total protein, numbers and amounts of proteins with a molecular weight of ,20 kDa, and degradation products of SP-A [137]. In the latter study, no effect of a 1 -AT on surfactant convertase, an alveolar enzyme hypothesised to be inhibited by serine protease inhibitors, was noted [138].…”

Section: Inhibition Of Free Elastase By Inhaled a 1 -At Inmentioning

confidence: 99%

Inhibition of airway proteases in cystic fibrosis lung disease

Griese¹,

Kappler²,

Gaggar³

et al. 2008

Eur Respir J

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Progressive lung disease determines the morbidity and mortality of cystic fibrosis (CF) patients.CF lung disease is characterised by endobronchial inflammation sustained by bacterial infections and an ongoing accumulation of airway neutrophils. Activated or necrotic neutrophils liberate proteases that cause damage to structural, cellular and soluble components of the pulmonary microenvironment.Among various proteases released by airway cells, elastase is considered to play the major role in CF lung disease. Based on this concept, several therapeutic approaches have been developed to inhibit free elastolytic activity, including small synthetic chemical compounds, semi-synthetic inhibitors and natural inhibitors of free elastase.The present review summarises and discusses the pathophysiological rationales, methodological requirements and clinical implications of inhibition of airway proteases in cystic fibrosis lung disease.

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Reduced proteolysis of surfactant protein A and changes of the bronchoalveolar lavage fluid proteome by inhaled α1-protease inhibitor in cystic fibrosis

Cited by 48 publications

References 25 publications

Role of Surfactant Proteins A, D, and C1q in the Clearance of Apoptotic Cells In Vivo and In Vitro: Calreticulin and CD91 as a Common Collectin Receptor Complex

Role of Surfactant Proteins A, D, and C1q in the Clearance of Apoptotic Cells In Vivo and In Vitro: Calreticulin and CD91 as a Common Collectin Receptor Complex

Surfactant protein A and other bronchoalveolar lavage fluid proteins are altered in cystic fibrosis

Inhibition of airway proteases in cystic fibrosis lung disease

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