Protein Kinase C Theta Inhibition Attenuates Lipopolysaccharide-Induced Acute Lung Injury through Notch Signaling Pathway via Suppressing Th17 Cell Response in Mice

AbstractAcute lung injury (ALI)/acute respiratory distress syndrome is characterized by increased pulmonary inflammation, where T helper 17 (Th17) cells play an important regulatory role. Notch signaling critically regulates Th17 differentiation and is known to be linked with proximal T cell by protein kinase C theta (PKC θ). We hypothesized that PKCθ inhibition could attenuate ALI by suppressing Th17 responsevia the Notch signaling pathway. Male C57BL/6 mice were treated with phosphate-buffered saline (PBS), lipopolysaccharide (LPS), LPS andN-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butyl ester (DAPT, a Notch signaling inhibitor), or LPS and PKC θ inhibitor (PI), and the bronchoalveolar lavage fluid (BALF), blood, and lung tissues were harvested at 48 h after the LPS challenge. CD4+ T cells were treated with DAPT or PI and harvested after 72  h. PKCθ inhibition markedly attenuated pathological changes and decreased the wet to dry weight ratio of the mouse lungs. The total cell and neutrophil counts, tumor necrosis factor-α (TNF- α) in BALF, myeloperoxidase activity in lung tissue, and the leukocyte count in whole blood were markedly reduced by PKCθ inhibition. The concentration of interleukin (IL)-17 and IL-22 in BALF, and the percentage of CD4+IL-17A+ T cells in the lungs were significantly downregulated by PKC θ inhibition. A similar trend was observed for the expression of retinoic acid-related orphan receptor gamma t and IL-23 receptor after PKCθ...
Source: Inflammation - Category: Allergy & Immunology Source Type: research