ZHANG Yan-Li, JIANG Cheng-Yu
Acute respiratory distress syndrome (ARDS) is a severe lung disease characterized by a cytokine storm, diffuse alveolar injury, increased pulmonary vascular permeability, and clinical manifestations of acute non-cardiogenic pulmonary edema and refractory hypoxemia (PaO2/FIO2 ≤ 300 mm Hg), which ultimately leads to multi-organ failure. The rapid onset, severity, and lack of effective treatments contribute to its high mortality rate, ranging from 30% to 70%, posing a significant public health threat. ARDS can be triggered by various etiologies, including severe infections (e.g., SARS-CoV, SARS-CoV-2, H5N1) and non-infectious causes. Current treatments are largely non-specific and focus on corticosteroids, traditional Chinese medicine, nutritional support, and mechanical ventilation.
The Berlin criteria (2012) are used for diagnosing ARDS, based on the timing of onset, hypoxemia, pulmonary edema, and associated radiological and physiological disorders. Recent studies suggested that biomarkers could enhance diagnostic sensitivity and specificity. For instance, elevated levels of Angiotensin II (Ang II) have been linked to the severity and prognosis of critical pneumonia, underscoring the importance of the renin-angiotensin system (RAS) in ARDS pathogenesis.
A key factor in the progression of ARDS is the disruption of the local RAS within lung tissues. Research has shown that activation of the Ang II-AT1R axis within the RAS contributes to lung injury. ACE2, a critical negative regulator of RAS, plays an essential role in mitigating lung injury caused by Ang II overproduction. Downregulation of ACE2 in animal models results in an imbalance in the RAS, leading to acute lung injury. Viral infections, including SARS-CoV, SARS-CoV-2, and avian influenza, as well as exposure to certain nanomaterials, can induce ARDS by reducing ACE2 levels, disrupting the RAS balance, particularly through activation of the Ang II-AT1R axis, which leads to an increase in Ang II.
We next discuss the exploration of potential therapeutic strategies involving RAS inhibitors, such as angiotensin receptor blockers (ARBs) and ACE2 supplementation. Studies have demonstrated that ARBs, including losartan, can significantly reduce lung injury and improve survival rates in animal models of ARDS induced by viral infections and other causes. Moreover, recombinant human ACE2 (rhACE2) has shown protective effects by lowering Ang II levels and alleviating pulmonary damage. Additionally, we discuss the therapeutic potential of ARBs in treating Multi-Organ Dysfunction Syndrome (MODS), as RAS dysregulation plays a critical role in organ injury. Clinical trials indicate that ARBs can improve outcomes in COVID-19 patients.
Despite potential adverse effects such as hypotension and electrolyte imbalance, ARBs remain a promising therapeutic option for both ARDS and MODS. Future studies should focus on further elucidating the molecular mechanisms underlying RAS regulation in different etiological contexts and developing personalized treatment strategies to optimize clinical outcomes. Overall, targeting RAS—particularly the Ang II-AT1R axis—represents a novel and promising approach for treating ARDS and MODS, offering a valuable therapeutic avenue for critically ill patients.
