Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies

Abstract

In recent years, the incidence of acute respiratory distress syndrome (ARDS) has been gradually increasing. Despite advances in supportive care, ARDS remains a significant cause of morbidity and mortality in critically ill patients. ARDS is characterized by acute hypoxaemic respiratory failure with diffuse pulmonary inflammation and bilateral edema due to excessive alveolocapillary permeability in patients with non-cardiogenic pulmonary diseases. Over the past seven decades, our understanding of the pathology and clinical characteristics of ARDS has evolved significantly, yet it remains an area of active research and discovery. ARDS is highly heterogeneous, including diverse pathological causes, clinical presentations, and treatment responses, presenting a significant challenge for clinicians and researchers. In this review, we comprehensively discuss the latest advancements in ARDS research, focusing on its heterogeneity, pathophysiological mechanisms, and emerging therapeutic approaches, such as cellular therapy, immunotherapy, and targeted therapy. Moreover, we also examine the pathological characteristics of COVID-19-related ARDS and discuss the corresponding therapeutic approaches. In the face of challenges posed by ARDS heterogeneity, recent advancements offer hope for improved patient outcomes. Further research is essential to translate these findings into effective clinical interventions and personalized treatment approaches for ARDS, ultimately leading to better outcomes for patients suffering from ARDS.

Fig. 1

70 years history of ARDS. Over the past 70 years, as research on ARDS has deepened, the definition of ARDS has gradually evolved, from “fluid overload” to the “Berlin definition”. This diagram shows important nodes in the evolution of ARDS definitions

Fig. 2

The pathological changes in ARDS. Acute respiratory distress syndrome affects not only pulmonary tissue but also extra-pulmonary tissues. Systemic pathological changes, such as immunoinflammation and immunothrombosis, occur throughout the body, and various cells are involved in these pathological changes including macrophage, monocyte, dendritic cell, neutrophil, eosinophil, T cell and endothelial cell. These changes are believed to contribute to cellular abnormalities within the pulmonary tissue, ultimately leading to damage to the alveolar-capillary barrier in ARDS. A variety of pulmonary pathological changes have been observed in the damaged lung tissue, including endothelial barrier dysfunction, the presence of cell-free hemoglobin, reduced resolution of pulmonary edema, cell death, cellular senescence, and cellular dysfunction. *M1: Proinflammatory phenotype of macrophages; NET: neutrophil extracellular trap; CFH: cell-free hemoglobin; AFC: alveolar fluid clearance

Fig. 3

Cellular pathological changes in pulmonary tissue. In the pathological process of ARDS, neutrophils, macrophages, alveolar epithelial cells, endothelial cells, etc., interact with each other through various cytokines, leading to pathological changes including efferocytosis, NET formation, senescence, apoptosis, pyroptosis, ferroptosis, etc. *DAMPS damage-associated molecular patterns, MCP monocyte chemoattractant protein, MAPK mitogen-activated protein kinase, IL interleukin, METTL methyltransferase, GPX glutathione-peroxidase, NET neutrophil extracellular trap

Fig. 4

MSC-based cell therapy in ARDS. MSCs have demonstrated strong capabilities in the treatment of ARDS, mainly including regulating the differentiation of alveolar epithelial cells, activating immune cells such as dendritic cells and macrophages to modulate immune function, repairing barrier function, and exerting anti-inflammatory and anti-apoptotic effects. *AECII type II alveolar epithelial cells, AECI type I alveolar epithelial cells, YAP Yes-associated protein, SPC surfactant protein C, LGALS3 galectin3, T1α podoplanin, FoxM Forkhead box (Fox) transcription factor family, DCs dendritic cells, HGF hepatocyte growth factor, PGE prostaglandin, Ach acetylcholine, AFC alveolar fluid clearance, CXCL C-X-C motif ligand, HO-1 heme oxygenase-1

Fig. 5

Extracellular vesicle-based therapy in ARDS. EVs secreted by MSCs or other cells primarily exert their effects by cargos such as miRNAs and mitochondria. These contents can alleviate alveolar-capillary barrier damage, and regulate macrophage function, thereby achieving anti-inflammatory and immune regulatory functions. *EVs extracellular vesicles, MSC mesenchymal stromal cell, epi-EVs epithelium-derived extracellular vesicles, endo-EVs endothelium-derived extracellular vesicles

Fig. 6

Main therapies of ARDS. With the deepening of research, the treatment methods of ARDS have developed many new factions based on traditional treatment methods. Clinical trials have confirmed the effectiveness of cell therapy in the treatment of ARDS, especially stem cells and cell components. In addition, targeted therapy with targeted immunotherapy as its core also shows good therapeutic effects. However, due to the significant heterogeneity of ARDS, emerging evidence has revealed that personalized medicine should be administered in different ARDS subphenotypes. *Targeted therapy: Targeted therapy for ARDS focuses on interrupting or modifying specific molecular, genetic, or cellular mechanisms underlying lung injury and inflammation, thus reducing symptoms and improving outcomes. Personalized therapy: Personalized treatment of ARDS refers to developing personalized treatment methods based on the individual characteristics of the patient, such as genetic makeup, medical history, and unique disease manifestations, to optimize treatment efficacy and minimize side effects. HFNO high-flow nasal cannula oxygen, NIV noninvasive ventilation, PEEP positive end-expiratory pressure, ARDS Acute respiratory distress syndrome, CARDS COVID-19 related acute respiratory distress syndrome, TNF-α tumor necrosis factor alpha, GM-CSF granulocyte-macrophage colony-stimulating factor, KGF keratinocyte Growth Factor, NET neutrophil extracellular trap, TNFSF14 lymphocyte-inducing protein, NLRP3 NOD-, LRR- and pyrin domain-containing 3, NF-κB nuclear factor kappa B, STAT signal transducer and activator of transcription, Nrf2: nuclear factor-E2-related factor 2