Incidence and Pathogenesis of Acute Lung Injury and the Acute Respiratory Distress Syndrome in Humans

Acute lung injury (ALI) and it’s more severe form, acute respiratory distress syndrome (ARDS), are conditions characterised by neutrophilic pulmonary inflammation, refractory hypoxaemia and diffuse alveolar damage. This work reports on the first UK based prospective study of the incidence and longer term mortality of ALI/ARDS in a general intensive care unit. Results reveal significant under recognition of this condition, which occurred in 12.5% of the ICU population (n=344). Hospital and 2 year mortality rates were 50-55% and 58-61% respectively. Neutrophils are central in the pathogenesis of ALI/ARDS. Neutrophil priming, a reversible process whereby the response of neutrophils to an activating stimulus is up-regulated by prior exposure to a priming agent, is a pre-requisite for neutrophil-mediated tissue damage. Comparisons of the trans-pulmonary gradient of several markers of neutrophil priming were made in different patient groups. Patients with sepsis but healthy lungs (n=6) were found to have a positive trans-pulmonary gradient with respect to neutrophil expression of CD62L, suggesting that CD62L ‘low’ (primed) neutrophils are being de-primed in the pulmonary circulation. In patients with ARDS this gradient was reversed, suggesting that neutrophils are being primed within the lung. This leads to the novel hypothesis that, in conditions such as sepsis, neutrophils primed systemically may be held in the pulmonary capillary bed and there allowed to de-prime, before being released in a quiescent state. Failure of this process may allow net accumulation of primed neutrophils in the lung with consequent lung injury. Currently there are no effective pharmacological therapies for ALI/ARDS, which is compounded by the relative lack of human models. An 18 month, prospective study of the incidence of ALI/ARDS post oesophagectomy revealed an incidence of 31% and suggested intra-operative one lung ventilation as a causative factor. Hence, patients undergoing oesophagectomy present an attractive model for future ALI/ARDS research.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of East Anglia

Year dc:date.issued

2013

Author dc:creator

• Singh, Nanak

Language dc:language

en