Regulated programmed cell death in acute lung injury: from pathogenesis to therapy

Abstract

Acute lung injury (ALI) is a common, life-threatening lung disease with a high mortality rate, primarily associated with acute and severe inflammation of the lungs. There are many factors that lead to ALI, and abnormally advanced regulated programmed cell death (RCD) is considered to be an important process in the pathological process of ALI. Various forms of RCD have been discovered in recent years, including apoptosis, necroptosis, autophagy, ferroptosis and pyroptosis. Unlike necrosis, RCD is an active cell death mediated by a series of gene expression events that is essential for eliminating unnecessary and damaged cells as well as defense mechanisms. Previous studies have shown that RCD has a strong relationship with ALI. Therefore, it is important to describe the role of RCD not only to enhance our understanding of the pathophysiological processes of ALI, but also to improve the functional recovery after ALI. This review reviews the roles and mechanisms of various RCD (apoptosis, pyroptosis, necroptosis, ferroptosis and autophagy) in ALI, and discusses the associations among various types of RCD. The aim is to explore the molecular mechanism behind SALI and find new targets for the treatment of ALI. This review will help us understand the various functions and mechanisms of RCD in the pathological process of ALI, and help us to treat various ALI of unknown etiology.

Keywords: acute lung injury; acute respiratory distress syndrome; pathological mechanism; programmed cell death; treatment.

Figure 1

Schematic diagram of intrinsic and extrinsic apoptotic pathways in ALI. The intrinsic pathway is initiated by the cell’s own response to damage, while the extrinsic pathway is activated by death receptors stimulated by immune system cells. When caspase3 (executor caspase) is activated, the two pathways converge, leading to cell apoptosis. This diagram was created on https://app.biorendercom.

Figure 2

Pyroptosis mechanism of ALI in pathological process. (A) In the typical inflammasome pathway, pathogen-associated molecular patterns or injection-associated molecular patterns such as viruses, bacteria, toxins, ATP, or ROS stimulate the inflammasome, which then activates caspase-1 to cleave GSDMD to form pores. (B) Direct activation of caspase-4/5/11 by Gramme-negative LPS followed by cleavage of GSDMD and pyroptosis in atypical inflammasome pathways. This diagram was created on https://app.biorendercom.

Figure 3

Details of the ferroptosis pathway in SALI pathology. (A) Macrophages engulf red blood cells and digest them into hemoglobin, which is further degraded into heme. Heme catabolizes to Fe (II) and Fe (III), which are released from macrophages or promote ROS production, resulting in ferroptosis. (B) Ferroptosis is caused by the inhibition of system Xc, leading to the termination of GSH biosynthesis and the inactivation of GPX4, followed by cell death through excess lipid ROS production. PUFAs-00H and Fe (II) promote ferroptosis of tumor cells mediated by the Fenton reaction. This diagram was created on https://app.biorendercom.

Figure 4

Schematic diagram of necroptosis in the pathological process of ALI. Necroptosis is initiated by cell surface death receptors (including FasRs, TNFR, IFN receptors, and TLRs) and intracellular ZBP1, and the downstream protein RHIM binds to RIPK3. Necrocorpuscles then form, leading to cell lysis. This diagram was created on https://app.biorendercom.

Figure 5

Schematic diagram of autophagy formation and activation during SALI pathology. This diagram was created on https://app.biorendercom.

Figure 6

Regulation of cell death pathways in ALI. This diagram includes four major signaling pathways that play important roles in the regulation of ALI. They are the PI3K/AKT signaling pathway, the NF-κB signaling pathway, the JAK/STAT signaling pathway, and the MAPK signaling pathway. This diagram was created on https://app.biorendercom.

Figure 7

Diagram of the relationship between different forms of RCD in ALI. This diagram was created on https://app.biorendercom.

Figure 8

Interplay network of cell death modalities in ALI. This diagram was created on https://app.biorendercom.