The Effects of Tumstatin on Vascularity, Airway Inflammation and Lung Function in an Experimental Sheep Model of Chronic Asthma

Abstract

Tumstatin, a protein fragment of the alpha-3 chain of Collagen IV, is known to be significantly reduced in the airways of asthmatics. Further, there is evidence that suggests a link between the relatively low level of tumstatin and the induction of angiogenesis and inflammation in allergic airway disease. Here, we show that the intra-segmental administration of tumstatin can impede the development of vascular remodelling and allergic inflammatory responses that are induced in a segmental challenge model of experimental asthma in sheep. In particular, the administration of tumstatin to lung segments chronically exposed to house dust mite (HDM) resulted in a significant reduction of airway small blood vessels in the diameter range 10+–20 μm compared to controls. In tumstatin treated lung segments after HDM challenge, the number of eosinophils was significantly reduced in parenchymal and airway wall tissues, as well as in the bronchoalveolar lavage fluid. The expression of VEGF in airway smooth muscle was also significantly reduced in tumstatin-treated segments compared to control saline-treated segments. Allergic lung function responses were not attenuated by tumstatin administration in this model. The data are consistent with the concept that tumstatin can act to suppress vascular remodelling and inflammation in allergic airway disease.

Tumstatin fragment selectively inhibits neutrophil infiltration in experimental asthma exacerbation

“…The significant reduction of tumstatin in lung tissue from asthmatic patients has been suggested to contribute to the pathogenesis of this disease by allowing for increased neovascularization, eosinophil influx and mucus production . This study shows for the first time a distinct role of tumstatin (CP17) in moderating experimental asthma exacerbations by alleviating neutrophil inflammatory profiles in vitro (ROS production, migration) and in vivo and adds to the accumulating body of evidence of col IV matrikines to play a vital role in ECM‐inflammatory crosstalk.…”

“…| 1489 influx and mucus production. 5,9,10,38 This study shows for the first time a distinct role of tumstatin (CP17) in moderating experimental asthma exacerbations by alleviating neutrophil inflammatory profiles in vitro (ROS production, migration) and in vivo and adds to the accumulating body of evidence of col IV matrikines to play a vital role in ECM-inflammatory crosstalk.…”

“…Effects of col IV NC1 domain fragments on leucocyte behaviour have been known for more than 20 years . Recently, the significant reduction of tumstatin in asthmatic lung biopsies has spurred further investigations by Burgess and colleagues on the exact function of tumstatin in mouse and sheep models of allergic asthma . Tumstatin itself and various active fragments contained in it conferred significant biological activity by reducing eosinophil infiltration, reduced mucus production, decreased levels of IL‐13 and VEGF and amelioration of bronchial hyperresponsiveness .…”

“…29,39 Recently, the significant reduction of tumstatin in asthmatic lung biopsies has spurred further investigations by Burgess and colleagues on the exact function of tumstatin in mouse and sheep models of allergic asthma. 5,9,38 Tumstatin itself and various active fragments contained in it conferred significant biological activity by reducing eosinophil infiltration, reduced mucus production, decreased levels of IL-13 and VEGF and amelioration of bronchial hyperresponsiveness. 5 Tumstatin's activity on microvascularization was extensively explored in the context of tumour growth; however, little to no evidence was available for asthma exacerbations.…”

“…5,8 Treatment of an experimental asthma mouse model with recombinant tumstatin resulted in a significant amelioration of bronchial hyperresponsiveness, infiltration with inflammatory cells, decreased vascular remodelling and reduced mucus production, 5 which was recently confirmed by a segmental allergen challenge model in a chronic house dust mite sheep model. 9 Additionally, Harkness et al 10 identified that tumstatin may also play an important role in the control of neutrophil inflammation. ECM fragments, which act independently of the parent molecule, are collectively assigned to a class of molecules termed matrikines.…”