New Role of Adult Lung c-kit⁺Cells in a Mouse Model of Airway Hyperresponsiveness

Abstract

Structural changes contribute to airway hyperresponsiveness and airflow obstruction in asthma. Emerging evidence points to the involvement of c-kit+ cells in lung homeostasis, although their potential role in asthma is unknown. Our aim was to isolate c-kit+ cells from normal mouse lungs and to test whether these cells can interfere with hallmarks of asthma in an animal model. Adult mouse GFP-tagged c-kit+ cells, intratracheally delivered in the ovalbumin-induced airway hyperresponsiveness, positively affected airway remodeling and improved airway function. In bronchoalveolar lavage fluid of cell-treated animals, a reduction in the number of inflammatory cells and in IL-4, IL-5, and IL-13 release, along with an increase of IL-10, was observed. In MSC-treated mice, the macrophage polarization to M2-like subset may explain, at least in part, the increment in the level of anti-inflammatory cytokine IL-10. After in vitro stimulation of c-kit+ cells with proinflammatory cytokines, the indoleamine 2,3-dioxygenase and TGFβ were upregulated. These data, together with the increased apoptosis of inflammatory cells in vivo, indicate that c-kit+ cells downregulate immune response in asthma by influencing local environment, possibly by cell-to-cell contact combined to paracrine action. In conclusion, intratracheally administered c-kit+ cells reduce inflammation, positively modulate airway remodeling, and improve function. These data document previously unrecognized properties of c-kit+ cells, able to impede pathophysiological features of experimental airway hyperresponsiveness.

Intratracheal administration of bone marrow c-kit+ cells offered hopes in ameliorating asthmatic pathologies via the control of miRNA-133 and -126

“…Consistent with our results, Spaziano and co-workers the intratracheal administration of 5 × 10 4 murine pulmonary c-kit cells had potential to suppress the production of cytokines IL-4, -5, and -13 with polarization of macrophages to M2-like phenotype orchestrated possibly in paracrine and/or juxtacrine manner. In addition, the local content of IL-10 was also increased post-c-kit transplantation [26] . The advantage of the current experiment is to investigate the potent anti-asthmatic activity of bone marrow c-kit cells (3 × 10 5 cell) compared to local c-kit lineage and to highlight the underlying role of distinct mi-RNAs in pulmonary tissue.…”

“…Of most notably, c-kit + cells belonging to stem cells have been shown to possess unique regenerative capacity and immuno-modulatory effects in animal cardiac tissues [22][23][24][25]. However, experiments and therapies based on c-kit + cells for airway in ammation are still in its infancy [26]. The current study targets to reveal the correlation between anti-in ammatory effects of c-kit positive cells and distinct miRNAs contributing to therapeutic paracrine outcome.…”

Nociceptin/Orphanin Fq in inflammation and remodeling of the small airways in experimental model of airway hyperresponsiveness

“…; Spaziano et al. ) but its effects during asthmatic airway hyperresponsiveness have not been clarified yet. Thus, we studied the role of the N/OFQ peptide in the inflammatory and remodeling process of the small airways, by using an ex vivo histological approach.…”

“…However, histopathological evidence from several studies has clearly shown that the inflammation in asthmatic subjects also involves the small airways (Wagner et al 1998). N/ OFQ protects against bronchial hyperresponsiveness and has immunomodulatory properties in the lung (Saetta et al 1985;Wagner et al 1998;Corsico et al 2003;Sullo et al 2013;Spaziano et al 2016) but its effects during asthmatic airway hyperresponsiveness have not been clarified yet. Thus, we studied the role of the N/OFQ peptide in the inflammatory and remodeling process of the small airways, by using an ex vivo histological approach.…”

“…Lung reactivity was assessed in an isolated and perfused mouse lung model (IPL-1), Hugo Sachs Elektronik -Harvard Apparatus, as described in details in Spaziano et al (2016) (Singh et al 2013). Mice were anesthetized with ketamine HCl 40 mg kg -1 i.p.…”