Alpha-1-antitrypsin and other proteinase inhibitors

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Since the end of the 1980s augmentation therapy with alpha-1 antitrypsin (AAT) from human plasma has been available for specific treatment of emphysema due to AAT deficiency. Intravenous augmentation therapy has demonstrated to be safe and weekly infusions of AAT have demonstrated to result in plasma AAT concentration above those considered protective for the lungs. Randomized, placebo-controlled clinical trials have confirmed a reduction in the decline in lung density in patients receiving augmentation therapy. This is the first example of an antiprotease effective in restoring the protease/antiprotease imbalance in the lungs and changing the natural history of congenital emphysema.

On the basis of the results obtained with the long-term infusion of AAT, there is growing interest in the possible use of antiprotease treatment in patients with smokers COPD. However, no drugs are yet available to increase antiprotease protection of the lower airways of smokers.

Highlights

► Protease/antiprotease imbalance is one of the recognized causes of pulmonary emphysema in smokers and patients with AAT deficiency. ► Augmentation therapy with intravenous AAT reduces the progression of loss of lung density in patients with congenital emphysema. ► Optimization of intravenous regimen must be made on an individual basis based on the pharmacokinetics of infused AAT. ► The search for novel antiproteases that could potentially be used in smokers COPD is an ongoing field of intense research.

Introduction

One of the main consequences of smoking is the development of progressive airflow limitation in a subset of susceptible smokers. Epidemiological studies have identified as much as 10% of adults with chronic obstructive pulmonary disease (COPD) [1] and the predominant pulmonary lesion in smokers with COPD is the enlargement of air spaces due to rupture of the alveoli, also known as pulmonary emphysema [2••]. Traditionally, this rupture has been attributed to the increase in proteases, particularly neutrophil elastase, released by activated neutrophils attracted to the alveoli by the inhaled substances included in tobacco smoke [3]. Since the lungs are directly exposed to the inhaled particles suspended in the air, a series of defense mechanisms have been developed to protect the lower airways from inhaled pollutants and irritants, among which alpha-1-antitrypsin (AAT) is the most important [4]. However, in most cases the protection provided by AAT may not be enough to compensate for the massive inhalation of tobacco smoke day after day and year after year. This situation is even more dramatic in patients with AAT deficiency whose airways are not even protected against the particles naturally suspended in the inhaled air and may develop emphysema without having received significant exposure to smoking [5].

The discovery of the emphysema related to AAT deficiency in 1963 led to the hypothesis of protease–antiprotease balance as the origin of this respiratory disease. In fact, it has been observed that elimination of AAT by immunoprecipitation of the fluid obtained by bronchoalveolar lavage produces an 80% loss in the capacity of elastase inhibition [5].

The terms protease and peptidase are synonyms and are used indistinctly to designate the enzymes which break the peptidic bonds of the proteins. In turn, at the site of action on the substrate the proteases divide into endopeptidases (or proteinases) which split the peptidic chains within, and exopeptidases which split the chains at the terminal ends [6].

Proteinases are classified into the following groups according to the order of the catalytic residues in their peptidic chain and the flanking sequences: serine proteinases, Threonine proteinases, cysteine proteinases, aspartile proteinases, metalloproteinases, glutamyl proteinases, and mixed (with a catalytic type serine, cysteine, threonine) [7]. According to this scheme, elastase (specific AAT substrate) is a protease or peptidase; or more concretely, a proteinase or endopeptidase and specifically a serine proteinase.

The demonstration of the importance of antiprotease defense of the lower airways in COPD has led to the investigation of substances with antiprotease activity for the prevention and treatment of COPD in smokers. The main and the only antiprotease currently available for the treatment of COPD is purified AAT obtained from blood donors for periodical intravenous infusion for the treatment of emphysema in patients with congenital severe AAT deficiency [8].

Section snippets

Alpha-1-antitrypsin deficiency

Alpha-1 antitrypsin, also known as alpha-1 proteinase inhibitor (α1-Pi) and SERPIN1 (Serine Protease Inhibitor, group A, member 1), is a medium size (6.7 × 3.2 nm), tissue hydrosoluble and diffusible circulating glycoprotein with a molecular weight of 52-kDa and a half-life in blood of up to 5 days [4]. The molecule is made up of a central chain of 394 amino acids and three lateral chains of ramified carbohydrates. The active site, which is constituted by methionine and serine at positions 359 and

Augmentation therapy. Biochemical efficacy

The purified preparation of AAT derived from donor plasma has been available for intravenous administration since 1987 [11]. It has been shown that the infused preparation maintains its enzymatic activity in both plasma and bronchoalveolar lavage [2••, 10]. Moreover, since a direct correlation exists between plasma concentrations of AAT and its pulmonary activity, treatment can be monitored by measuring minimum plasma concentrations at steady state (Cmin), also called trough concentrations [11

Clinical efficacy of AAT augmentation therapy

The slow progression of pulmonary emphysema requires large and prolonged clinical trials to demonstrate any significant efficacy in changing the course of the decline in forced expiratory volume in 1 second (FEV1) [15]. The characteristics of AAT deficiency make it extremely difficult to perform such a large trial [12]. The first randomized double-blind placebo-controlled clinical trial compared treatment with human AAT and placebo; the dosage regimen studied was 250 mg/kg/28 days. This trial

Criteria for initiating augmentation therapy

Augmentation therapy should only be prescribed to patients with severe AAT deficiency, a PiZZ phenotype, or a rare deficient variant and functional evidence of pulmonary emphysema [2••, 10]. This therapy is not indicated in heterozygous PiMZ or PiSZ patients [19]. It has no effect on liver disease associated with this deficiency. Since blood derivatives may contain traces of IgA, and those patients with IgA deficiency may have circulating anti-IgA antibodies, the presence of IgA deficiency must

Other antiproteases

The deficiency in AAT is the best example of the imbalance between proteases and antiproteases in the lungs; however, even nondeficient smokers may develop emphysema due to insufficient antiprotease protection and an excess of proteases and oxidants. Existing AAT for human administration is not a feasible treatment for smokers COPD; therefore, the search for small-molecule protease inhibitors, particularly those with elastolytic activity, is a field of intense research. Oral neutrophil elastase

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (40)

  • American Thoracic Society/European Respiratory Society Statement

    Standards for the diagnosis and management of individuals with alpha1-antitrypsin deficiency

    Am J Respir Crit Care Med

    (2003)
  • L.T. Spencer et al.

    Role of human neutrophil peptides in lung inflammation associated with alpha1-antitrypsin deficiency

    Am J Physiol Lung Cell Mol Physiol

    (2004)
  • D.A. Lomas et al.

    Alpha1-antitrypsin deficiency. 4: Molecular pathophysiology

    Thorax

    (2004)
  • J.K. Stoller et al.

    Alpha1-antitrypsin deficiency

    Lancet

    (2005)
  • C. López-Otín et al.

    Proteases and multifunctional enzymes in life and disease

    J Biol Chem

    (2008)
  • A. Janoff

    Inhibition of human granulocyte elastase by serum alpha-1-antitrypsin

    Am Rev Respir Dis

    (1972)
  • R. Vidal et al.

    Guidelines for the diagnosis and management of alpha-1-antitrypsin deficiency

    Arch Bronconeumol

    (2006)
  • A.R. Tonello et al.

    Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies

    Ther Adv Respir Dis

    (2010)
  • J.K. Stoller et al.

    Augmentation therapy with alpha-1-antitrypsin: patterns of use and adverse events

    Chest

    (2003)
  • D. Soy et al.

    Alpha-1-antitrypsin deficiency: optimal therapeutic regimen based on population pharmacokinetics

    Thorax

    (2006)
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