The Effect of Augmentation Therapy on Bronchial Inflammation in α1-Antitrypsin Deficiency

Abstract

alpha1-Antitrypsin (AAT) deficiency predisposes to bronchitis and emphysema associated with neutrophilic airway inflammation. The efficacy of augmentation therapy has not been proven clinically or by demonstrating an effect on airway inflammation. We treated 12 patients with four infusions of Prolastin (60 mg/kg) at weekly intervals and monitored both the serum and secretion concentrations of AAT as well as markers of neutrophilic inflammation, including myeloperoxidase, elastase, and the neutrophil chemoattractants interleukin-8 and leukotriene B(4). Serum AAT rose and was maintained above the protective threshold. In addition, AAT concentrations in the sputum rose from a mean of 0.17 microM (SEM +/- 0.04) before therapy to concentrations similar to nondeficient subjects (0.43 +/- 0.12) 1 week after the first infusion (p < 0.01). This was associated with a reduction in elastase activity (p < 0.002) and the chemoattractant leukotriene B(4) (p < 0.02), which fell from a median baseline value of 13.46 nM (range, 4.17-55.00) to 8.62 nM (4.23-21.59) the day following the last infusion. Although median values for myeloperoxidase and interleukin-8 also fell, the changes failed to achieve statistical significance. In summary, short-term therapy with AAT increased lung secretion concentrations and was associated with a fall in leukotriene B(4), which is thought to be central to the airway inflammation of AAT deficiency.

Desmosine as a biomarker of elastin degradation in COPD: current status and future directions

“…In this context, biochemical markers changing quickly following a therapeutic intervention, such as the decrease in sputum levels of leukotriene B 4 , interleukin-8 or neutrophil elastase after a few weeks of supplementation therapy with i.v. a 1 -AT [60], although correlated with the disease's inflammatory processes, cannot be considered a replacement for true clinical outcomes.…”

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

“…However, despite the observed clinical effects of AAT, further proof of the mechanism of action of augmentation therapy is required (42). Moreover, although AAT augmentation therapy has been shown to affect sputum levels of LTB 4 (43), the potential of AAT as a BLT1 antagonist is a novel concept. Consequently, this study has identified a pathogenic mechanism associated with AATD and illustrates the anti-inflammatory efficiency of AAT augmentation therapy by modulation of the LTB 4 / BLT1 pathway in human neutrophils.…”

Leukotriene A4 Hydrolase – An Evolving Therapeutic Target

“…Consistent with these biological observations, a variety of inflammatory diseases have been associated with the over-production of leukotriene B 4 . Some of these diseases are sepsis [47][48][49][50], shock [51,52], cystic fibrosis [53][54][55][56][57], coronary artery disease [58][59][60] connective tissue disease [19,[61][62][63][64][65], and COPD [66][67][68]. The biosynthesis of leukotriene B 4 is initiated by the conversion of arachidonic acid to leukotriene A 4 , which requires sequential actions by 5-lipoxygenase and 5-lipoxygenase activating protein.…”