Human models of acute lung injury

Abstract

Acute lung injury (ALI) is a syndrome that is characterised by acute inflammation and tissue injury that affects normal gas exchange in the lungs. Hallmarks of ALI include dysfunction of the alveolar-capillary membrane resulting in increased vascular permeability, an influx of inflammatory cells into the lung and a local pro-coagulant state. Patients with ALI present with severe hypoxaemia and radiological evidence of bilateral pulmonary oedema. The syndrome has a mortality rate of approximately 35% and usually requires invasive mechanical ventilation. ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis. Although animal models of ALI have been developed, none of them fully recapitulate the human disease. The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies. Improved animal models and the development of human in vivo and ex vivo models are therefore required. In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome.

Assessment of pulmonary oxygen toxicity: Relevance to professional diving; a review

“…When neonates or adults were ventilated with 100% oxygen for ≥ 30 h, denuded alveolar type 1 cells, oedematous endothelial capillary cell swelling, necrosis of the respiratory epithelium, and squamous metaplasia of tracheal and bronchial mucosa was found. Furthermore, deposition of eosinophilic slough within the bronchioles, and oedema within the alveola and interstitium was reported (Anderson et al, 1973;Bellingan, 2002;Brewis, 1969;Fisher et al, 1984;Proudfoot et al, 2011;Schuster and Kollef, 1996). Consequently, the proteinaceous oedema fluid became organized within the alveoli with the formation of hyaline membranes on the denuded membrane (Bellingan, 2002;Claireaux, 1975;Fisher et al, 1984;Schuster and Kollef, 1996;Sevitt, 1974).…”

Acute respiratory distress syndrome

“…33,34 These investigations need to be performed with a view to designing a step-wise approach to testing novel therapeutics in this particularly challenging patient group. Finally, phenotyping patients with a view to predicting drug class response may further help to establish disease modifying therapies.…”

ARDS following oesophagectomy: a comparison of two trials

“…[5][6][7] However, this high complication rate, alongside the planned nature of surgery and the clear timing of the surgical insult, makes oesophagectomy a potentially useful model to undertake trials to reduce perioperative complications. 8 Both the Beta Agonists in Lung Injury Trial-Prevention (BALTI-P), 9 which completed recruitment in 2011, and the Vitamin D to Prevent Acute Lung Injury Following Oesophagectomy (VINDALOO) trials, completed in 2015, 10 used oesophagectomy as a model of ARDS. We observed that the incidence of ARDS in the VINDALOO (8 out of 68, 11.8%) cohort was substantially lower than in the BALTI-P (83 out of 331, 25.1% and 14 out of 61, 23%) substudy (see the Methods section below), independent of a pharmacological effect of the agents trialled, suggesting that there had been changes between the groups that were expected a priori to be similar.…”