Abstract
Introduction: Inflammation is central in pathogenesis of lung disease in alpha-1 antitrypsin (A1AT) deficiency. Phospholipid transfer protein (PLTP) prevents airway inflammation; however, in chronic obstructive pulmonary disease (COPD), serine proteases cleave PLTP. We propose that A1AT augmentation therapy exerts novel anti-inflammatory effects by enhancing PLTP activity in the airways.
Methods: PLTP activity was measured in bronchoalveolar fluid (BALF) and plasma of healthy non-smokers, healthy smokers, non-A1AT COPD patients (all PiMM) and A1AT deficient COPD patients (all PiZZ). PLTP levels were also determined in BALF and plasma of individuals receiving normal (60 mg/kg) and high-dose (120 mg/kg) A1AT augmentation. A1AT protein isolated from the plasma of PiMM and PiZZ subjects as incubated with COPD BALF prior to combination with recombinant PLTP. PLTP cleavage was investigated.
Results: PLTP activity was comparable in the plasma of healthy non-smokers, smokers, PiMM and PiZZ COPD patients. However, BALF PLTP activity was significantly reduced in both COPD cohorts and smokers as compared to healthy individuals. A1AT isolated from plasma of PiMM individuals protected PLTP from proteolytic cleavage while A1AT from plasma of PiZZ individuals did not have the same protective effect. Weekly administration of 120 mg/kg A1AT significantly enhanced PLTP activity levels in BALF of A1AT deficient patients, which coincided with reduced inflammation.
Conclusions: A1AT therapy prevents PLTP cleavage and preserves its activity thereby enhancing its anti-inflammatory activity. Enhancing airway PLTP activity could have therapeutic potential in A1AT deficiency.
- Copyright ©ERS 2015
