Tumstatin fragment selectively inhibits neutrophil infiltration in experimental asthma exacerbation
Background: Asthma is a chronic inflammatory disease with structural changes present. Burgess and colleagues recently found tumstatin markedly reduced in adult asthmatic lung tissue compared with nonasthmatics. ECM fragments such as tumstatin are named matrikines and act independently of the parent molecule. The role of Col IV matrikines in neutrophil inflammation (eg. exacerbation in asthma) has not been investigated to date. Severe adult asthma phenotypes are dominated by neutrophilic inflammation and show a high frequency of severe exacerbations. Objective: This study sought to investigate the role of a novel active region within tumstatin (CP17) and its implication in neutrophil inflammatory responses related to asthma exacerbation. Methods: For reactive oxygen production, isolated neutrophils were preincubated with peptides or vehicle for 1 hour and stimulated (PMA). Luminescence signal was recorded (integration over 10 seconds) for 1.5 hours. Neutrophil migration was performed according to the SiMA protocol. Mice were sensitized to OVA/Alumn by intraperitoneal (i.p.) injections. Mice were then treated with CP17, vehicle (PBS) or scrambled peptide (SP17) after OVA exposure (days 27 and 28, polyI:C stimulation). All animals were killed on day 29 with lung function measurement, histology and lavage. Results: CP17 decreased total ROS production rate to 52.44% (0.5 mmol/L, P < 0.05 vs SP17), reduced the in vitro directionality (vs SP17, P = 1 × 10−6) and migration speed (5 mmol/L, P = 1 × 10−3). In vivo application of CP17 decreased neutrophil inflammation ~1.8‐fold (P < 0.001 vs SP17) and reduced numbers of mucus‐producing cells (−29%, P < 0.05). Conclusion: CP17 reduced the ROS production rate, migrational speed and selectively inhibited neutrophil accumulation in the lung interstitium and lumen. Clinical relevance: CP17 may serve as a potential precursor for drug development to combat overwhelming neutrophil inflammation.