Pseudomonas Aeruginosa Induced Cell Death in Acute Lung Injury and Acute Respiratory Distress Syndrome

Abstract

Pseudomonas aeruginosa is an important opportunistic pathogen responsible for the cause of acute lung injury and acute respiratory distress syndrome. P. aeruginosa isthe leading species isolated from patients with nosocomial infection and is detected in almost all the patients with long term ventilation in critical care units. P. aeruginosa infection is also the leading cause of deleterious chronic lung infections in patients suffering from cystic fibrosis as well as the major reason for morbidity in people with chronic obstructive pulmonary disease. P. aeruginosa infections are linked to diseases with high mortality rates and are challenging for treatment, for which no effective remedies have been developed. Massive lung epithelial cell death is a hallmark of severe acute lung injury and acute respiratory distress syndrome caused by P. aeruginosa infection. Lung epithelial cell death poses serious challenges to air barrier and structural integrity that may lead to edema, cytokine secretion, inflammatory infiltration, and hypoxia. Here we review different types of cell death caused by P. aeruginosa serving as a starting point for the diseases it is responsible for causing. We also review the different mechanisms of cell death and potential therapeutics in countering the serious challenges presented by this deadly bacterium.

Keywords: Pseudomonas aeruginosa; acute lung injury/acute respiratory distress syndrome; apoptosis; cell death; ferroptosis; lung infection.

Figure 1

General classification of cell death. The broad classification is programmed and unprogrammed. The programmed cell death is subclassified as apoptotic and non-apoptotic, with apoptotic consisting of apoptosis, while non-apoptotic consisting of ferroptosis, pyroptosis, anoikis, NETosis, and necroptosis. Unprogrammed cell death has necrosis as the mechanism (all figures were created using Biorender.com).

Figure 2

Schema for the mechanisms for different types of cell deaths. Part (a) displays two important pathways for apoptosis, namely intrinsic and extrinsic pathways, both converging at caspase-3 as the executioner pathway. Part (b) shows the three underlying pathways for pyroptosis involving caspases 1,3,4,5, and 11. Part (c) is the schematic representation for NETosis. Part (d) exhibits the two pathways for anoikis, intrinsic and extrinsic, respectively. Part (e) outlines the mechanistic pathways associated with ferroptosis, promotion of lipid peroxide formation being one path and inhibition of reduction of lipid peroxide being the other. TNF/TNFR signaling pathway for necroptosis via MLKL phosphorylation is displayed in part (f). Finally, part (g) represents the different stages in a general necrosis mechanism.

Figure 3

Schematic representation for the different cell death mechanisms caused due to P. aeruginosa infection. Part (a) consists of four important pathways for apoptosis, part (b) displays ExoT induced as well as activated P38-JNK induced anoikis, part (c) focuses on the two pathways associated with pyroptosis, part (d) is a cartoon representation of NEtosis pathway. Finally, part (e) is a single mechanism for P. aeruginosa induced ferroptosis involving peroxide formation and reactive oxygen species (ROS) generation, since ferroptosis is a newer cell death mechanism still being investigated for additional pathways.