Ulinastatin promotes macrophage efferocytosis and ameliorates lung inflammation via the ERK5/Mer signaling pathway

Abstract

Acute lung injury (ALI) is a pneumonic response characterized by neutrophil infiltration. Macrophage efferocytosis is the process whereby macrophages remove apoptotic cells, and is required for ALI inflammation to subside. The glycoprotein ulinastatin (UTI) has an anti-inflammatory effect during the acute stages of ALI, but its effect on efferocytosis and the subinflammatory stage of ALI is unclear. Extracellular signal-regulated kinase 5 (ERK5) is a key protein in efferocytosis, and we thus hypothesized that it may be activated by UTI to regulate efferocytosis and the resolution of pneumonia. To test this hypothesis, here we monitored phagocytosis of macrophages through in vivo and in vitro experiments. Pulmonary edema, neutrophil infiltration, protein exudation, and inflammatory factor regression were observed on days 1, 3, 5, and 7 in vivo. RAW264.7 cells were pretreated with different concentrations of UTI and ERK5 inhibitors, and the expression of tyrosine-protein kinase Mer (Mer) protein on macrophage membrane was detected. UTI increased the phagocytosis of apoptotic neutrophils by macrophages in vitro and in vivo, and promoted the resolution of pneumonia. The protein expression of ERK5 and Mer increased with UTI concentration, while the expression of Mer was down-regulated by ERK5 inhibitors. Therefore, our results suggest that UTI enhances efferocytosis and reduces lung inflammation and injury through the ERK5/Mer signaling pathway, which may be one of the targets of UTI in the treatment of lung injury.Acute lung injury (ALI) is a critical clinical illness of common occurrence and is a pneumonic reaction characterized by neutrophil infiltration [1]. The pathophysiological process of ALI can be roughly divided into the acute inflammatory stage and the subsiding inflammatory stage. In the subsiding phase of inflammation, macrophages directly engulf and clear apoptotic neutrophils to repair damaged tissues, a process called efferocytosis, which promotes the recovery of lung epithelial and endothelial functions and the reconstruction of lung tissue structure. If apoptotic cells are not cleared in time, many intracellular danger signaling molecules are released by secondary cell necrosis, which further hinders tissue repair. Therefore, promoting the regression of pneumonia will shorten the pathophysiological process of ALI and reduce lung injury [2,3].Ulinastatin (UTI), a commonly used drug in clinical practice, is an endogenous molecule with actions against infectious pathogens and its pharmacological Abbreviations ALI, acute lung injury; ERK5, extracellular signalregulated kinase 5; Mer, tyrosine-protein kinase Mer; UTI, ulinastatin.

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“…33 Additionally, UTI can also influence the expression levels of ERK/MER, affecting macrophage apoptosis, thereby impacting immune-inflammatory responses. 42 It is worth noting that oxidative stress is closely associated with inflammatory responses. Studies have demonstrated that oxidative stress leads to an excessive generation of ROS and a decrease in the levels and activity of antioxidant enzymes, resulting in an imbalance between the oxidative and antioxidant systems.…”

Bone and Extracellular Signal-Related Kinase 5 (ERK5)

“…ERK5 is a key protein in macrophage endocytosis. The glycoprotein ulinastatin (UTI) increases ERK5 levels, enhances endocytosis through the ERK5/Mer signaling pathway, and reduces lung inflammation and injury [47]. However, some studies present contrasting findings.…”

Early Endothelial Signaling Transduction in Developing Lung Edema

“…Considering the transition from the early postlesional inflammatory stage to the subsiding phase leading to and remodeling of the lung structure, the role of ulinastatin was shown to promote the process of efferocytosis, namely the clearing process of apoptotic neutrophils operated by macrophages to favor repair [ 76 ].…”