Activated protein C inhibits neutrophil migration in allergic asthma: a randomised trial

Abstract

Asthma patients show evidence of a procoagulant state in their airways, accompanied by an impaired function of the anticoagulant protein C system. We aimed to study the effect of recombinant human activated protein C (rhAPC) in allergic asthma patients.We conducted a randomised, double-blind, placebo-controlled, proof-of-concept study in house dust mite (HDM) allergic asthma patients. Patients were randomised to receive intravenous rhAPC (24 µg·kg ; n=12) or placebo (n=12) for 11 h. 4 h after the start of infusion, a first bronchoscopy was performed to challenge one lung segment with saline (control) and a contralateral segment with a combination of HDM extract and lipopolysaccharide (HDM+LPS), thereby mimicking environmental house dust exposure. A second bronchoscopy was conducted 8 h after intrabronchial challenge to obtain bronchoalveolar lavage fluid (BALF).rhAPC did not influence HDM+LPS induced procoagulant changes in the lung. In contrast, rhAPC reduced BALF leukocyte counts by 43% relative to placebo, caused by an inhibitory effect on neutrophil influx (64% reduction), while leaving eosinophil influx unaltered. rhAPC also reduced neutrophil degranulation products in the airways.Intravenous rhAPC attenuates HDM+LPS-induced neutrophil migration and protein release in allergic asthma patients by an effect that does not rely on coagulation inhibition.

How to achieve safe, high-quality clinical studies with non-Medicinal Investigational Products? A practical guideline by using intra-bronchial carbon nanoparticles as case study

“…Dosages were calculated according to the European Medicines Agency (EMA) First-In-Man (FIM) guidelines based on the No Observed Adverse Effect Level (NOAEL) in non-clinical safety studies adjusted with allometric factors. These dosages are comparable with the mean exposure concentration of PM 2.5 (particles smaller than 2.5 μm) during public fireworks at New Year’s Day at the first hour of the year, as measured by the Dutch National Air Quality Monitoring Network and previous research in the Netherlands by Strak et al [ 17 ] We used the well-described and safe method of bronchial segmental challenge [ 18 , 19 ] to deliver the nanoparticles to the lungs. An important advantage of this model, as compared to inhalation of diesel exhaust in an inhalation chamber, is that the exposure is limited to only one component (carbon nano particles) in only one subsegment of the lung, thereby reducing the risk of generalized bronchoconstriction.…”

“…An important advantage of this model, as compared to inhalation of diesel exhaust in an inhalation chamber, is that the exposure is limited to only one component (carbon nano particles) in only one subsegment of the lung, thereby reducing the risk of generalized bronchoconstriction. In the past we safely performed bronchial segmental challenges with house dust mite allergen and lipopolysaccharide in healthy subjects as well as patients with mild asthma [ 18 , 19 ]. Based upon the thorough analysis of the final product to be used and the careful considerations regarding the dosage and method of administration, the institutional ethics committee approved the study.…”

Advanced Role of Neutrophils in Common Respiratory Diseases

“…Biopharmaceutical has become a new treatment for asthma in recent years. Recombinant human activated protein C (rhAPC) could attenuate HDM + LPS-induced neutrophil migration in allergic asthma [91]. Another recombination protein, recombinant human IL-4, could inhibit airway inflammation in bronchial asthma by reducing the cytokines and inflammatory cells including neutrophils [92].…”

Asthma is associated with enhanced thrombin formation and impaired fibrinolysis

“…On the other hand, higher levels of a 2 -macroglobulin can display a procoagulant activity due to the formation of complexes with activated protein C. This might lead to a loss of its anticoagulant activity and enhanced thrombin generation [30]. A recent pilot study showing attenuation of neutrophil migration and protein release in allergic asthmatics treated with recombinant human activated protein C might indicate that suppressed thrombin formation could indeed be beneficial in this disease [31]. Moreover, anticoagulant therapy is not used in asthma treatment nowadays, although the beneficial effect of heparin on airways inflammation and asthma symptoms is well-known [5].…”