To date no definite treatment exists for acute lung injury (ALI), only supportive
therapy, among which mechanical ventilation is an important tool; however
ventilation itself may exacerbate the underlying injury, termed ventilator-induced lung
injury (VILI). The pro-inflammatory cytokine tumour necrosis factor alpha (TNF) has
been consistently implicated in the pathogenesis of ALI/VILI, however clinical trials
with anti-TNF therapy failed to improve the outcome.
TNF acts on two cell-surface receptors (TNFRs), p55 and p75, and knock-out
studies in ALI/VILI indicate they have directly opposing roles, i.e. promoting or
protecting against pulmonary oedema, respectively, but it remains unclear where
these signalling mechanisms take place, being the endothelial or epithelial side of
the alveolar-capillary membrane. This project had two main aims: to characterise the
expression profile and roles of TNF receptor subtypes on each side of the alveolarcapillary
membrane and to modulate ALI progression in mouse models by targeting
individual TNFRs accordingly.
Characterisation studies on freshly harvested mouse pulmonary endothelial
cells (PECs) using flow cytometry indicated expression of both receptors with
dominance of p55. Knock-out and pharmacological inhibition studies in vivo and in
vitro, respectively, found p55 to be the major mediator of TNF-induced adhesion
molecule expression on PECs, with a similar but less potent role for p75 that varied
across adhesion molecules. Endotoxaemia resulted in rapid shedding of p55 on
PECs while expression of p75 was preserved, indicating that the relative role of the
receptors may change during inflammatory conditions.
Specific inhibition of intraalveolar p55 signalling by domain antibodies
significantly attenuated both pulmonary oedema and inflammation in mouse models
of VILI and acid-aspiration.
These data offer new, potentially clinically applicable insights into the
involvement of TNFR biology in ALI and the novel domain antibody technology may
open a new therapeutic approach for patients who suffer from, or at risk of ALI.