Selective tumour necrosis factor receptor-1 inhibition in acute lung injury: a new hope or a false dawn?

A complex myriad of aetiologies and pathologies coalesce within the clinical syndrome of acute respiratory distress syndrome (ARDS) often obfuscating our understanding of the disorder. Amidst the complexity, acute lung inflammation stands out as the fundamental unifying pathophysiology underlying ARDS. A better understanding of the mechanisms driving inflammation in the lung and the ensuing response from the innate immune system, endothelial and epithelial barriers are key to developing disease-modifying drugs in ARDS. Targeted inhibition of proinflammatory molecules such as tumour necrosis factor (TNF)-α would seem a logical and fruitful line of investigation for disease-modifying intervention in ARDS. As suggested by its name, TNF-α was first described as a mediator in abrogating malignant proliferation of cancerous cells.1 Since then, TNF-α has also been identified as a key cytokine in modulating inflammation. TNF-α is mainly produced by macrophages and monocytes, but it is released by most cells, including endothelial cells, epithelial cells and most other leucocytes. A pleiotropic cytokine, TNF-α has a wide range of biological activities. TNF-α has been implicated as a chemoattractant for neutrophils and eosinophils, as a mediator of apoptosis and a major stimulant of other proinflammatory cytokine release.2 In ARDS, elevated levels of TNF-α are found in both plasma and bronchioalveolar lavage (BAL).3 4 In the lungs, TNF-α expression directly leads to increased endothelial permeability5 6 and downregulates epithelial sodium channel expression leading to impaired alveolar fluid clearance.7 Aside from ARDS, TNF-α is also a critical mediator in other inflammatory conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. Moreover, in these diseases, inhibitors of TNF-α are now in widespread therapeutic use, setting a precedent for their use in ARDS. As a ligand, TNF-α binds to two members of TNF-receptor superfamily: TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2). TNFR1 is a transmembrane receptor with …