Ibudilast, a Phosphodiesterase-4 Inhibitor, Ameliorates Acute Respiratory Distress Syndrome in Neonatal Mice by Alleviating Inflammation and Apoptosis

Abstract

Departmental sources Background:Acute respiratory distress syndrome (ARDS) is a sudden and serious disease with increasing morbidity and mortality rates. Phosphodiesterase 4 (PDE4) is a novel target for inflammatory disease, and ibudilast (IBU), a PDE4 inhibitor, inhibits inflammatory response. Our study investigated the effect of IBU on the pathogenesis of neonatal ARDS and the underlying mechanism related to it. Material/Methods:Western blotting was performed to analyze the expression levels of PDE4, CXCR4, SDF-1, CXCR5, CXCL1, inflammatory cytokines, and proteins related to cell apoptosis. Hematoxylin-eosin staining was performed to observe the pathological morphology of lung tissue. Pulmonary edema score was used to assess the degree of lung water accumulation after pulmonary injury. Enzyme-linked immunosorbent assay (ELISA) was used to assess levels of inflammatory factors (TNF-a, IL-1b, IL-6, and MCP-1) in serum. TUNEL assay was used to detect apoptotic cells. Results:Increased expression of PDE4 was observed in an LPS-induced neonatal ARDS mouse model, and IBU ameliorated LPS-induced pathological manifestations and pulmonary edema in lung tissue. In addition, IBU attenuated the secretion of inflammatory cytokines by inactivating the chemokine axis in the LPS-induced neonatal ARDS mouse model. Finally, IBU significantly reduced LPS-induced cell apoptosis in lung tissue. Conclusions:IBU, a PDE4 inhibitor, protected against ARDS by interfering with pulmonary inflammation and apoptosis. Our findings provide a novel and promising strategy to regulate pulmonary inflammation in ARDS.

Lipocalin-2 silencing suppresses inflammation and oxidative stress of acute respiratory distress syndrome by ferroptosis via inhibition of MAPK/ERK pathway in neonatal mice

“…The histological changes in lung tissue, such as inflammatory infiltration, hemorrhage, and alveolar wall edema were observed in LPS-stimulated mice. However, mice that were injected through caudal veins with of LCN2 silencing show a reduced histological damage, which is consistent with previous studies [ 26 , 27 ]. In addition, sh-LCN2 treatment resulted in lower weight ratio of wet and dry lung tissue, suggesting that inhibition of LCN2 has a potential therapeutic effect on LPS-exposed pulmonary damage.…”

Acute Ethanol Challenge Differentially Regulates Expression of Growth Factors and miRNA Expression Profile of Whole Tissue of the Dorsal Hippocampus

“…In contrast, ibudilast produced small effects on IL-6, BDNF, and FGF2 in the same direction as ethanol in the hippocampus, and seemed to potentiate most effects of ethanol in the amygdala. Although these effects would seem to conflict with the extant literature showing that ibudilast reduced the pro-inflammatory profile in the brain ( Lee et al, 2012 ; Schwenkgrub et al, 2017 ; Yang et al, 2020 ), it should be noted that the neuroimmune gene expression profile evoked by experimenter-administered ethanol also shares characteristic anti-inflammatory suppression of TNFα and IL-1β, similar to anti-inflammatory glucocorticoid exposure ( Barnum et al, 2008 ; Vore et al, 2017 ). It should also be noted that only a single dose of ibudilast was tested against a single high dose of ethanol exposure, so it may be prudent to conduct more elaborate dose-response functions in future studies.…”

“…For example, phosphodiesterase-4 (PDE4) inhibition is broadly associated with reduced inflammation, especially brain cytokine expression, including growth factor expression ( Rolan et al, 2009 ). Several rodent models have demonstrated that inflammatory challenges which produced enhancements in proinflammatory cytokines such as IL-1β and TNFα were blunted with administration of PDE inhibitors ( Mizuno et al, 2004 ; Crilly et al, 2011 ; Lee et al, 2012 ; Schwenkgrub et al, 2017 ; Yang et al, 2020 ). Furthermore, this ablation of inflammation was often accompanied by enhancements in growth factors ( Mizuno et al, 2004 ; Schwenkgrub et al, 2017 ).…”

Acute Lung Functional and Airway Remodeling Effects of an Inhaled Highly Selective Phosphodiesterase 4 Inhibitor in Ventilated Preterm Lambs Exposed to Chorioamnionitis

“…First, PDE inhibition has been shown to decrease pulmonary inflammation in various animal models of hyperoxia-induced BPD [ 10 ], meconium aspiration syndrome [ 11 , 12 ] and lavage-induced lung injury [ 13 ]. In a recent study on mice exposed to lipopolysaccharide, PDE4 inhibitor Ibudilast ameliorated acute RDS by alleviating inflammation [ 14 ]. In a rodent lung lavage model, an intratracheally administered PDE4 inhibitor prevented further hyaline membrane formation and infiltration of neutrophil leukocytes [ 15 ].…”