Electrophilic Fatty Acid Derivatives in Asthma
Condition: Asthma; Electrophilic Fatty Acids
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 1

Summary: 
      Asthma is an inflammatory disease, which means it causes swelling in the lungs to cause
      shortness of breath and/or wheezing. There are several asthma medications that help to reduce
      this problem.

      The objective of this research study is to characterize the presence of electrophilic fatty
      acids in the bronchial airway of subjects with controlled asthma at baseline and after
      treatment with Aspirin, Indomethacin, or no treatment at all. The presence of electrophilic
      fatty acids may indicate inflammation. Aspirin and Indomethacin are known to respectively
      increase and inhibit the formation of electrophilic fatty acids. By gaining a better
      understanding of how electrophilic fatty acids work and how they respond to different
      treatment, researchers hope to be able to find better ways to lessen airway inflammation in
      asthma in the future.
    

Detailed description: 
      Relevant to asthma, the chemical identities and potent anti-inflammatory signaling actions of
      endogenously-produced Electrophilic Fatty acid OXidation products (EFOXs) have recently been
      described. Endogenous EFOXs include nitro and alpha and beta-unsaturated ketone derivatives
      of unsaturated fatty acids that are generated as byproducts of a) fatty acid oxidation and
      nitration by inflammatory-derived reactive species and b) enzymatic fatty acid oxygenation
      reactions catalyzed by cyclooxygenase-2 and lipoxygenases. Recent data reveal that multiple
      salutary post-translational protein modifications are induced by EFOXs. Specifically, the
      covalent adduction of functionally-significant thiols in signaling proteins occurs, with
      these reactions modulating critical inflammatory signaling pathways. These signaling proteins
      include the nuclear lipid receptor PPARg and the redox-sensitive transcription factors NF
      kappaB and Keap1/Nrf2. This proposed research investigates the concept that the reversible
      reaction of EFOXs with critical transcription factors results in the regulation of adaptive
      responses to inflammation.

      In this clinical study, bronchoalveolar lavage fluid (BAL) will be obtained from asthmatics
      treated with COX-2 inhibitors that enhance (aspirin) and inhibit (indomethacin) COX-2
      dependent EFOX generation, as well as from those assigned to no intervention. BAL will be
      obtained from healthy, non-smoking adults with controlled asthma having at least a 12%
      increase in FEV1 after short-acting bronchodilator treatment or a positive methacholine
      response (reduction in FEV1 ≥ 20% at or before 16 mg/ml). A total of 30 asthmatic subjects
      will be randomized (10 per arm) to a) aspirin, b) indomethacin or c) no intervention groups
    

Intervention name(s): Aspirin; Indomethacin
Intervention type(s): Drug; Drug
Intervention description(s): 500 mg/8 h for 5 days; 25 mg/8 h for 5 days
Intervention MeSH terms: Aspirin; Indomethacin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Asthma; Electrophilic Fatty Acids; Inflammation