Abstract
The aim of the present study was to investigate the regulatory mechanism of nuclear factor (NF)-κB on polymorphonuclear neutrophil (PMN) accumulation and the inflammatory response in lung tissues with acute respiratory distress syndrome (ARDS), as well as the therapeutic effect of pyrrolidine dithiocarbamate (PDTC). Mouse models of ARDS were established by intraperitoneal injection of lipopolysaccharide (LPS). BALB/c mice were divided into control, LPS and PDTC + LPS groups. The expression of PMN adhesion molecules, CD11b/CD18 and intercellular adhesion molecule-1 (ICAM-1), were detected by immunohistochemistry, while the protein expression levels of NF-κB p65 in the lung tissue were analyzed by western blot analysis. In addition, flow cytometry was used to investigate the apoptosis rate of PMNs in the bronchoalveolar fluid, and the expression levels of interleukin (IL)-1β, IL-8 and tumor necrosis factor (TNF)-α and myeloperoxidase (MPO) activity were also determined. Following an intraperitoneal injection of LPS, alveolar septum rupture, pulmonary interstitial hyperemia and PMN infiltration in the alveolar was observed. The protein expression of p65 in the pulmonary cytoplasm decreased, while the expression of p65 in the nucleus increased. The levels of IL-8, IL-1β and TNF-α increased and the high expression status was maintained for 24 h. As the time increased, CD11b/CD18 and ICAM-1 expression increased, as well as MPO activity, while the apoptosis of PMNs was delayed. Compared with the LPS group, the expression of p65 in the pulmonary cytoplasm and the PMN apoptosis rate increased following PDTC intervention, while the expression of p65 in the nucleus decreased, as well as the expression levels of the cytokines and MPO activity. Therefore, PDTC reduced the production of inflammatory cytokines via the NF-κB pathway, which reduced the activation of PMNs in the lung tissue and promoted PMN apoptosis.
Highlights
The main pathological changes in acute respiratory distress syndrome (ARDS) are diffuse pulmonary interstitial and alveolar edema, caused by increased pulmonary microvascular permeability
Previous studies have demonstrated that a large number of polymorphonuclear neutrophils (PMNs) accumulate in the lung tissue and release inflammatory cytokines, including interleukin (IL)‐1β, IL‐8 and tumor necrosis factor (TNF)‐α, when the body fights against infection or trauma, which plays an important role in initiating and maintaining the inflammatory response [4,5]
Under the stimulation of activated factors, including LPS, TNF‐α and IL‐8, CD11b/CD18 is a heterodimer of the αM (CD11b)/CD18 interacts with its ligand intercellular adhesion molecule‐1 (ICAM‐1) on pulmonary vascular endothelial cell surfaces, activating PMNs [19] and firmly adhering to the endothelial cells
Summary
The main pathological changes in acute respiratory distress syndrome (ARDS) are diffuse pulmonary interstitial and alveolar edema, caused by increased pulmonary microvascular permeability. The underlying pathogenesis of ARDS is excessively uncontrolled inflammatory responses that are mediated by various inflammatory cytokines, treatment has limited efficacy [2]. Previous studies have demonstrated that a large number of polymorphonuclear neutrophils (PMNs) accumulate in the lung tissue and release inflammatory cytokines, including interleukin (IL)‐1β, IL‐8 and tumor necrosis factor (TNF)‐α, when the body fights against infection or trauma, which plays an important role in initiating and maintaining the inflammatory response [4,5]. PMNs are important effector cells in ARDS, and the infiltration and activation of PMNs involve a complex process that includes the recruitment, adhesion and chemotaxis of PMNs. In addition, the process is associated with PMN adhesion molecules CD11b/CD18, pulmonary vascular endothelial intercellular adhesion molecule‐1 (ICAM‐1) and PMN chemokines, such as IL‐8.
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