Background: Tumor necrosis factor-α (TNF) is strongly implicated in the development of
acute respiratory distress syndrome (ARDS), but its potential as a therapeutic target has been
hampered by its complex biology. TNF signals through two receptors, p55 and p75, which
play differential roles in pulmonary edema formation during ARDS. We have recently
shown that inhibition of p55 by a novel domain antibody (dAb™) attenuated ventilator36
induced lung injury. In the current study we explored the efficacy of this antibody in mouse
models of acid-induced lung injury, to investigate the longer consequences of treatment.

Methods: We employed two acid-induced injury models, an acute ventilated model and a
resolving spontaneously breathing model. C57BL/6 mice were pretreated intratracheally or
intranasally with p55-targeting dAb or non-targeting ‘dummy’ dAb, 1 or 4 hours before acid
instillation.

Results: Acid instillation in the dummy dAb group caused hypoxemia, increased respiratory
system elastance, pulmonary inflammation and edema in both the ventilated and resolving
models. Pretreatment with p55-targeting dAb significantly attenuated physiological markers
of ARDS in both models. p55-targeting dAb also attenuated pulmonary inflammation in the
ventilated model, with signs that altered cytokine production and leukocyte recruitment
persisted beyond the very acute phase.

Conclusions: These results demonstrate that the p55-targeting dAb attenuates lung injury and
edema formation in models of ARDS induced by acid aspiration, with protection from a
single dose lasting up to 24 hours. Together with our previous data, the current study lends
support towards the clinical targeting of p55 for patients with, or at risk of ARDS.