IL-1β processing in mechanical ventilation-induced inflammation is dependent on neutrophil factors rather than caspase-1.
OBJECTIVE
Mechanical ventilation can cause ventilator-induced lung injury, characterized by a sterile inflammatory response in the lungs resulting in tissue damage and respiratory failure. The cytokine interleukin-1β (IL-1β) is thought to play an important role in the pathogenesis of ventilator-induced lung injury. Cleavage of the inactive precursor pro-IL-1β to form bioactive IL-1β is mediated by several types of proteases, of which caspase-1, activated within the inflammasome, is the most important. Herein, we studied the roles of IL-1β, caspase-1 and neutrophil factors in the mechanical ventilation-induced inflammatory response in mice.


METHODS
Untreated wild-type mice, IL-1αβ knockout and caspase-1 knockout mice, pralnacasan (a selective caspase-1 inhibitor)-treated mice, anti-keratinocyte-derived chemokine (KC)-treated mice and cyclophosphamide-treated neutrophil-depleted wild-type mice were ventilated using clinically relevant ventilator settings (tidal volume 8 ml/kg). The lungs and plasma were collected to determine blood gas values, cytokine profiles and neutrophil influx.


RESULTS
Mechanical ventilation resulted in increased pulmonary concentrations of IL-1β and KC and increased pulmonary neutrophil influx compared with non-ventilated mice. Ventilated IL-1αβ knockout mice did not demonstrate this increase in cytokines. No significant differences were observed between wild-type and caspase-1-deficient or pralnacasan-treated mice. In contrast, in anti-KC antibody-treated mice and neutropenic mice, inflammatory parameters decreased in comparison with ventilated non-treated mice.


CONCLUSIONS
Our results illustrate that IL-1 is indeed an important cytokine in the inflammatory cascade induced by mechanical ventilation. However, the inflammasome/caspase-1 appears not to be involved in IL-1β processing in this type of inflammatory response. The attenuated inflammatory response observed in ventilated anti-KC-treated and neutropenic mice suggests that IL-1β processing in mechanical ventilation-induced inflammation is mainly mediated by neutrophil factors.
Department of Anaesthesiology, RUNMC, Nijmegen, 6500 HB, The Netherlands, Kim.Timmermans@radboudumc.nl.
Kim
K
Timmermans
Selina Ei
SE
van der Wal
Michiel
M
Vaneker
Jeroen Awm
JA
van der Laak
Mihai G
MG
Netea
Peter
P
Pickkers
Gert Jan
GJ
Scheffer
Leo Ab
LA
Joosten
Matthijs
M
Kox