Tumor necrosis factor-α driven inflammation in alpha-1 antitrypsin deficiency: a new model of pathogenesis and treatment

ABSTRACT

Alpha-1 antitrypsin (AAT) deficiency (AATD) has traditionally been thought of as a genetic disorder characterized by lung destruction and early emphysema in a low AAT, and high neutrophil elastase (NE) environment in the lungs of affected individuals. Recently, a growing body of evidence has emerged to support the hypothesis that tumor necrosis factor alpha (TNF-α) is essential in the pathogenesis of both genetic AATD and non-genetic chronic obstructive pulmonary disease (COPD). Reports have highlighted the importance of TNF-α driven immune cell dysfunction in the development of lung disease in AATD. The authors discuss the role of AAT as a key modulator of TNF-α signaling firstly in the setting of AATD and secondly in other conditions where AAT augmentation therapy has potential utility as a novel therapy.

KEYWORDS:

• Alpha-1 antitrypsin
• alpha-1 antitrypsin deficiency
• chronic obstructive pulmonary disease
• TNF-α
• ADAM-17
• neutrophils
• inflammation
• alpha-1 antitrypsin augmentation therapy

Key Issues

• AAT is a plasma glycoprotein and is the canonical serine protease inhibitor. AATD is the most common form of genetically determined emphysema.

• Increasingly it has been recognized that the AAT protein has pleiotropic functions that mediate a broad range of anti-inflammatory activities beyond protease inhibition.

• AAT has been shown to impact upon the TNF-α signaling axes including inhibition of ADAM-17 enzyme activity and TNF-α secretion. Moreover, the observation that AAT can inhibit apoptotic factors has widened our perspective on the role of AAT in the pathogenesis of emphysema.

• Currently the standard treatment for AATD is to administer exogenous plasma purified human AAT. In vivo studies have demonstrated that therapy decreases lung density decline and TNF-α expression. Administering aerosolized or intravenous AAT has been of tremendous interest in recent years and an attractive prospect in the future will be investigating the potential of treating other TNF-α associated pulmonary and non-pulmonary diseases with AAT.

Financial & competing interests disclosure

The authors were supported by the Alpha-1 Foundation (U.S.), the Medical Research Charities Group/Health Research Board, and the Programme for Research in Third-Level Institutes (PRTLI) administered by the Higher Education Authority. K Hurley is a recipient of the European Alpha-1-antitrypsin Laurell’s Training Award (eALTA) 2011. E Reeves is a recipient of a Research Grant from the US Alpha-1 Foundation. Professor NG McElvaney is a recipient of funding from the Medical Research Charities Group/Health Research Board, and the Programme for Research in Third-Level Institutes (PRTLI) administered by the Higher Education Authority The authors have no other relevant affiliations or financial involvement with an organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.