Low-tidal-volume Mechanical Ventilation Induces a Toll-like Receptor 4-dependent Inflammatory Response in Healthy Mice

Background: Mechanical ventilation (MV) can induce ventilator-induced lung injury. A role for proinflammatory pathways has been proposed. The current studies analyzed the roles of Toll-like receptor (TLR) 4 and TLR2 involvement in the inflammatory response after MV in the healthy lung.

Methods: Wild-type (WT) C57BL6, TLR4 knockout (KO), and TLR2 KO mice were mechanically ventilated for 4 h. Bronchoalveolar lavage fluid was analyzed for presence of endogenous ligands. Lung homogenates were used to investigate changes in TLR4 and TLR2 expression. Cytokines were measured in lung homogenate and plasma, and leukocytes were counted in lung tissue.

Results: MV significantly increased endogenous ligands for TLR4 in bronchoalveolar lavage fluid and relative messenger RNA expression of TLR4 and TLR2 in lung tissue. In lung homogenates, MV in WT mice increased levels of keratinocyte-derived chemokine, interleukin (IL)-1alpha], and IL-1beta]. In TLR4 KO mice, MV increased IL-1alpha] but not IL-1beta], and the increase in keratinocyte-derived chemokine was less pronounced. In plasma, MV in WT mice increased levels of IL-6, keratinocyte-derived chemokine, and tumor necrosis factor alpha]. In TLR4 KO mice, MV did not increase levels of IL-6 or tumor necrosis factor alpha], and the response of keratinocyte-derived chemokine was less pronounced. MV in TLR2 KO mice did not result in different cytokine levels compared with WT mice. In WT and TLR2 KO mice, but not in TLR4 KO mice, MV increased the number of pulmonary leukocytes.