The repair process of airway epithelium involves cell migration, spreading, proliferation and re-differentiation. Objective: Cellular and molecular responses to tracheal brush induced injury were investigated using a rabbit model. Methods: Eighteen New Zealand white rabbits were divided into uninjured and injured groups. After tracheal brushing, the animals were maintained in the laboratory before being sacrificed at given time points (1, 12 hours, 3, 7, and 21 days). The trachea of each rabbit was retrieved and preserved before being subjected to haematoxylin and eosin staining and real time PCR. Results: After injury, the remained epithelial cells underwent an instant response by proliferating and migrating into the damaged site. This finding was in accordance with the proliferative and migration activity-related gene expression results (MMP-9, TIMP1, vimentin, and ß-integrin). The increased activity of these genes was crucial at the early time points, as it encouraged the remaining cells to repopulate the damaged area. Conclusions: Continuous regulation of MMP-9, vimentin and ß-integrin plays important roles in promoting cellular homing especially the cells bordering the lesion to migrate and repair of the damaged ECM. Thus, this activation enhanced regeneration and repair of the damaged tracheal epithelium as early as 1 h and complete at 21 d following injury.
Airway stem/progenitor epithelial cells (AECs) are notable for their differentiation capacities in response to lung injury. Our previous finding highlighted the regenerative capacity of AECs following transplantation in repairing tracheal injury and reducing the severity of alveolar damage associated acute lung injury in a rabbit model. The goal of this study is to further investigate the potential of AECs to re-populate the tracheal epithelium and to study their stimulatory effect on inhibiting pro-inflammatory cytokines, epithelial cell migration and proliferation, and epithelial-to-mesenchymal transition (EMT) process following tracheal injury. Two in vitro culture assays were applied in this study; the direct co-culture assay that involved a culture of decellularised tracheal epithelium explants and AECs in a rotating tube, and indirect co-culture assay that utilized microporous membrane-well chamber system to separate the partially decellularised tracheal epithelium explants and AEC culture. The co-culture assays provided evidence of the stimulatory behaviour of AECs to enhance tracheal epithelial cell proliferation and migration during early wound repair. Factors that were secreted by AECs also markedly suppressed the production of IL-1β and IL-6 and initiated the EMT process during tracheal remodelling.
Aerosol-based cell delivery technique via intratracheal is an effective route for delivering transplant cells directly into the lungs. An aerosol device known as the MicroSprayer(®) Aerosolizer is invented to transform liquid into an aerosol form, which then can be applied via intratracheal administration for drug delivery. The device produces a uniform and concentrated distribution of aerosolized liquid. Using the capability of MicroSprayer(®) Aerosolizer to transform liquid into aerosol form, our group has designed a novel method of cell delivery using an aerosol-based technique. We have successfully delivered skin-derived fibroblast cells and airway epithelial cells into the airway of a rabbit with minimum risk of cell loss and have uniformly distributed the cells into the airway. This chapter illustrates the application of aerosol device to deliver any type of cells for future treatment of lung diseases.
No single animal model can reproduce all of the human features of both acute and chronic lung diseases. However, the rabbit is a reliable model and clinically relevant facsimile of human disease. The similarities between rabbits and humans in terms of airway anatomy and responses to inflammatory mediators highlight the value of this species in the investigation of lung disease pathophysiology and in the development of therapeutic agents. The inflammatory responses shown by the rabbit model, especially in the case of asthma, are comparable with those that occur in humans. The allergic rabbit model has been used extensively in drug screening tests, and this model and humans appear to be sensitive to similar drugs. In addition, recent studies have shown that the rabbit serves as a good platform for cell delivery for the purpose of stem-cell-based therapy.
The therapeutic use of mesenchymal stromal cells (MSCs) represents a promising alternative clinical strategy for treating acute and chronic lung disorders. Several preclinical reports demonstrated that MSCs can secrete multiple paracrine factors and that their immunomodulatory properties can support endothelial and epithelial regeneration, modulate the inflammatory cascade and protect lungs from damage. The effects of MSC transplantation into patients suffering from lung diseases should be fully evaluated through careful assessment of safety and associated risks, which is a prerequisite for translation of preclinical research into clinical practice. In this article, we summarize the current status of preclinical research and review initial MSC-based clinical trials for treating lung injuries and lung disorders.