Tumstatin regulates the angiogenic and inflammatory potential of airway smooth muscle extracellular matrix

Abstract

The extracellular matrix (ECM) creates the microenvironment of the tissue; an altered ECM in the asthmatic airway may be central in airway inflammation and remodelling. Tumstatin is a collagen IV‐derived matrikine reduced in the asthmatic airway wall that reverses airway inflammation and remodelling in small and large animal models of asthma. This study hypothesized that the mechanisms underlying the broad asthma‐resolving effects of tumstatin were due to autocrine remodelling of the ECM. Neutrophils and endothelial cells were seeded on decellularized ECM of non‐asthmatic (NA) or asthmatic (A) airway smooth muscle (ASM) cells previously exposed to tumstatin in the presence or absence of a broad matrix metalloproteinase inhibitor, Marimastat. Gene expression in NA and A ASM induced by tumstatin was assessed using RT‐PCR arrays. The presence of tumstatin during ECM deposition affected neutrophil and endothelial cell properties on both NA and A ASM‐derived matrices and this was only partly due to MMP activity. Gene expression patterns in response to tumstatin in NA and A ASM cells were different. Tumstatin may foster an anti‐inflammatory and anti‐angiogenic microenvironment by modifying ASM‐derived ECM. Further work is required to examine whether restoring tumstatin levels in the asthmatic airway represents a potential novel therapeutic approach.

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.…”

“…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.…”

Fibulin-1c regulates transforming growth factor–β activation in pulmonary tissue fibrosis

“…Peptide products resulting from ECM degradation are not necessarily inert and may have immunomodulatory effects. Peptides from ECM degradation induce the proliferation, migration, and MMP production and ECM deposition of airway smooth muscle (ASM) cells and myofibroblasts (53,54). Protein fragments generated by MMP activity are increased in the serum of patients with IPF compared with healthy controls and are associated with disease progression (55).…”

“Locked” cancer cells are more sensitive to chemotherapy

“…After that, the exploitation of the drug was terminated. Surprisingly, recent studies unveiled that the drug could inhibit the metastasis, alleviate the inflammation, and regulate the immune system via inhibition of MMPs. Indeed, our previous reports indicated the drug blocked the metastasis significantly .…”