Human amnion epithelial cells for the prevention of ventilation-induced lung injury
Creators: name: Melville, Jacqueline Mary
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: In Australia, approximately 7% of all neonates require some form of assisted ventilation. Mechanical ventilation of neonates results in ventilation-induced lung injury (VILI), most likely due to immune responses to tissue damage caused by ventilation. Infants who develop bronchopulmonary dysplasia (BPD) have greater inflammation, are born at younger gestational ages, and spend longer on a ventilator than infants who do not. Animal models of preterm mechanical ventilation have demonstrated the initial histological lung damage and inflammation believed to underlie the pathogenesis of BPD, a multifactorial disease. A reduction in the inflammatory response to mechanical ventilation could prevent the subsequent lung injury. One potential immunomodulatory treatment is human amnion epithelial cells (hAECs), which are known to modify inflammatory responses to injury. Human AECs are multipotent cells that can alter immune responses to injury. Lung injury, as a result of intrauterine inflammation, is reduced with the administration of hAECs to fetal sheep. Similarly, hAECs reduce lung injury following in utero ventilation of fetal sheep. The global aim of this thesis was to characterise the inflammatory response to mechanical ventilation and to assess a novel cell therapy for the prevention of this inflammation and subsequent VILI. In chapter 3, the inflammatory response to short-term injurious mechanical ventilation and the influence of hAEC administration on the inflammatory response in preterm lambs was investigated. We found that mechanical ventilation with high tidal volume (targeting 15 ml/kg) and no positive end expiratory pressure (PEEP) for the first 15 min caused lung inflammation and injury. Ventilation increased pulmonary activation of B cells and indicators of leukocyte migration. The administration of hAECs reduced lung injury and B cell activation in the airways. These data demonstrate the potential of hAECs for reducing the initial pulmonary inflammatory response to injurious mechanical ventilation. Preterm infants have immature, surfactant-deficient lungs. Some mechanically ventilated preterm infants are administered exogenous surfactant to reduce alveolar surface tension and prevent collapse. Cell therapy is rapidly nearing translation into treatment to improve lung development and prevent the progression to BPD in preterm infants who require invasive respiratory support. Combination therapy with prophylactic surfactant is a logical combination. In chapter 4, we investigated the effect of surfactant exposure on the phenotype and function of hAECs in vitro. We found that following incubation with exogenous surfactant hAECs maintained their normal phenotype and viability. The immunosuppressive ability of hAECs, namely inhibition of T cell proliferation, was maintained following surfactant exposure. Differentiation of hAECs into lung epithelial-like cells was maintained following surfactant exposure. These data demonstrate that surfactant does not alter viability or function of hAECs. Thus, a combination therapy of hAECs and surfactant is possible and may be efficacious in the prevention of VILI. Extended periods of time on a ventilator increase the risk of developing BPD. Infants who develop BPD are ventilated for long periods despite use of gentle ventilation strategies. Evaluation of the safety and efficacy of hAEC administration in a clinically relevant animal model is critical before clinical trials are conducted in infants. In chapter 5 we investigated the effect of hAEC administration on the inflammatory response following long-term (48 h) gentle mechanical ventilation (targeting 5-7 ml/kg tidal volume, 6 cmH2O PEEP and 3 ml surfactant). We found hAEC administration did not alter histological lung injury and inflammation. The administration of hAECs reduced monocyte activation in the lung. In the blood hAEC administration did not alter immune phenotype. However, ventilation alone increased the proportion of CD4 T cells but T cell proliferation was reduced, indicating T cell anergy. The activation of B cells decreased following ventilation, regardless of treatment. These data in chapter 5 demonstrate that hAEC are not detrimental to the lambs following 48 h of ventilation, and that administration of hAECs reduces pulmonary immune activation, but does not prevent histological lung injury. In conclusion, these studies increase our understanding of hAECs’ potential role in reducing VILI. These data suggest that in circumstances of injurious ventilation hAECs may reduce inflammation. Additionally, hAEC administration does not detrimentally affect the heath of ventilated lambs and can be used in conjunction with current clinical treatments and procedures.