scholarly journals Characterisation of a type II functionally-deficient variant of alpha-1-antitrypsin discovered in the general population

2018 ◽  
Author(s):  
Mattia Laffranchi ◽  
Emma L. K. Elliston ◽  
Fabrizio Gangemi ◽  
Romina Berardelli ◽  
David A. Lomas ◽  
...  
Keyword(s):  
Substantial Reduction ◽  
Lung Parenchyma ◽  
Intrinsic Activity ◽  
Type Ii ◽  
Cellular Models ◽  
Reactive Centre Loop ◽  
Severe Reduction ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

AbstractLung disease in alpha-1-antitrypsin deficiency (AATD) results from dysregulated proteolytic activity, mainly by neutrophil elastase (HNE), in the lung parenchyma. This is the result of a substantial reduction of circulating alpha-1-antitrypsin (AAT) and the presence in the plasma of inactive polymers of AAT. Moreover, some AAT mutants have reduced intrinsic activity toward HNE, as demonstrated for the common Z mutant, as well as for other rarer variants. Here we report the identification and characterisation of the novel AAT reactive centre loop variant Gly349Arg (p.G373R) present in the ExAC database. This AAT variant is secreted at normal levels in cellular models of AATD but shows a severe reduction in anti-HNE activity. Biochemical and molecular dynamics studies suggest it exhibits unfavourable RCL presentation to cognate proteases and compromised insertion of the RCL into β-sheet A. Identification of a fully dysfunctional AAT mutant that does not show a secretory defect underlines the importance of accurate genotyping of patients with pulmonary AATD manifestations regardless of the presence of normal levels of AAT in the circulation. This subtype of disease is reminiscent of dysfunctional phenotypes in antithrombin and C1-inibitor deficiencies so, accordingly, we classify this variant as the first pure functionally-deficient (type II) AATD mutant.

scholarly journals Rare Lung Diseases I – Lymphangioleiomyomatosis

2006 ◽  
Vol 13 (7) ◽  
pp. 375-380 ◽  
Author(s):  
Stephen C Juvet ◽  
David Hwang ◽  
Gregory P Downey
Keyword(s):  
Lung Diseases ◽  
Focal Point ◽  
Lung Parenchyma ◽  
Great Promise ◽  
Childbearing Age ◽  
Antitrypsin Deficiency ◽  
Cystic Changes ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Rare Lung Diseases ◽  
Alpha 1 Antitrypsin

The present article is the first in a series that will review selected rare lung diseases. The objective of this series is to promote a greater understanding and awareness of these unusual conditions among respirologists. Each article will begin with a case that serves as a focal point for a discussion of the pathophysiology and management of the particular condition. The first article is on lymphangioleiomyomatosis (LAM); subsequent articles will focus on pulmonary alveolar proteinosis, alpha-1-antitrypsin deficiency and primary ciliary dyskinesia.LAM is a rare, progressive and (without intervention) often fatal interstitial lung disease that predominantly affects women of childbearing age. LAM is characterized by progressive interstitial infiltration of the lung by smooth muscle cells, resulting in diffuse cystic changes of the lung parenchyma. The molecular basis of this disorder has been delineated over the past five years and LAM is now known to be a consequence of mutations in the tuberous sclerosis genes. This knowledge, combined with advances in our understanding of the signalling pathways regulated by these genes, has given rise to potential molecular therapies that hold great promise for treating this devastating disease.

scholarly journals How Do Mechanics Guide Fibroblast Activity? Complex Disruptions during Emphysema Shape Cellular Responses and Limit Research

2021 ◽  
Vol 8 (8) ◽  
pp. 110
Author(s):  
Mathew N. Leslie ◽  
Joshua Chou ◽  
Paul M. Young ◽  
Daniela Traini ◽  
Peta Bradbury ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Lung Parenchyma ◽  
Mechanical Environment ◽  
Novel Treatments ◽  
Antitrypsin Deficiency ◽  
Emphysematous Lung ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
The Impact

The emphysema death toll has steadily risen over recent decades, causing the disease to become the third most common cause of death worldwide in 2019. Emphysema is currently incurable and could be due to a genetic condition (Alpha-1 antitrypsin deficiency) or exposure to pollutants/irritants, such as cigarette smoke or poorly ventilated cooking fires. Despite the growing burden of emphysema, the mechanisms behind emphysematous pathogenesis and progression are not fully understood by the scientific literature. A key aspect of emphysematous progression is the destruction of the lung parenchyma extracellular matrix (ECM), causing a drastic shift in the mechanical properties of the lung (known as mechanobiology). The mechanical properties of the lung such as the stiffness of the parenchyma (measured as the elastic modulus) and the stretch forces required for inhalation and exhalation are both reduced in emphysema. Fibroblasts function to maintain the structural and mechanical integrity of the lung parenchyma, yet, in the context of emphysema, these fibroblasts appear incapable of repairing the ECM, allowing emphysema to progress. This relationship between the disturbances in the mechanical cues experienced by an emphysematous lung and fibroblast behaviour is constantly overlooked and consequently understudied, thus warranting further research. Interestingly, the failure of current research models to integrate the altered mechanical environment of an emphysematous lung may be limiting our understanding of emphysematous pathogenesis and progression, potentially disrupting the development of novel treatments. This review will focus on the significance of emphysematous lung mechanobiology to fibroblast activity and current research limitations by examining: (1) the impact of mechanical cues on fibroblast activity and the cell cycle, (2) the potential role of mechanical cues in the diminished activity of emphysematous fibroblasts and, finally, (3) the limitations of current emphysematous lung research models and treatments as a result of the overlooked emphysematous mechanical environment.

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