Acute respiratory distress syndrome heterogeneity and the septic ARDS subgroup

Abstract

Acute respiratory distress syndrome (ARDS) is an acute diffuse inflammatory lung injury characterized by the damage of alveolar epithelial cells and pulmonary capillary endothelial cells. It is mainly manifested by non-cardiogenic pulmonary edema, resulting from intrapulmonary and extrapulmonary risk factors. ARDS is often accompanied by immune system disturbance, both locally in the lungs and systemically. As a common heterogeneous disease in critical care medicine, researchers are often faced with the failure of clinical trials. Latent class analysis had been used to compensate for poor outcomes and found that targeted treatment after subgrouping contribute to ARDS therapy. The subphenotype of ARDS caused by sepsis has garnered attention due to its refractory nature and detrimental consequences. Sepsis stands as the most predominant extrapulmonary cause of ARDS, accounting for approximately 32% of ARDS cases. Studies indicate that sepsis-induced ARDS tends to be more severe than ARDS caused by other factors, leading to poorer prognosis and higher mortality rate. This comprehensive review delves into the immunological mechanisms of sepsis-ARDS, the heterogeneity of ARDS and existing research on targeted treatments, aiming to providing mechanism understanding and exploring ideas for accurate treatment of ARDS or sepsis-ARDS.

Keywords: acute respiratory distress syndrome (ARDS); heterogeneity; immune system; precision therapy; sepsis.

Figure 1

Sepsis can cause ARDS through circulating immune cells and cytokines. After the host undergoes the attack causing sepsis, circulating immune cells are activated and abundant inflammatory mediators are released in the blood. These cells and cytokines injure the vascular endothelium systemically, including the capillary endothelium of the lung. When the endothelium of pulmonary capillaries is damaged, activated immune cells migrating into the lung aggravate the pulmonary inflammatory response and eventually lead to ARDS occurrence.

Figure 2

When the systemic system is in a state of sepsis, the inflammation in the circulation will affect various tissues and organs, in which the lung is often affected. (A) When the cytokine storm occurs in the circulation, cytokines can enter the lung through the broken endothelium and cause damage to the lung tissue. (B) Sepsis induces lung injury through inflammatory signaling pathways, including nuclear factor kappa B (NF-κB), JAK/STAT, and mitogen-activated protein kinase (MAPK). (C) In addition to the activation of resident macrophages in the alveoli, neutrophils, macrophages, a few lymphocytes and monocytes can also enter the alveoli through the damaged endothelium, causing inflammation and tissue damage. (D) With the massive activation of inflammation caused by sepsis, there will be apoptosis and depletion of immune cells, which is manifested as immune paralysis. The apoptosis, dysfunction and exhaustion of T cells are mainly mediated by the PD-1 pathway.