Abstract
Acute respiratory distress syndrome (ARDS) is characterized by massive inflammation, increased vascular permeability and pulmonary edema. Mortality due to ARDS remains very high and even in the case of survival, acute lung injury can lead to pulmonary fibrosis. The renin–angiotensin system (RAS) plays a significant role in these processes. The activities of RAS molecules are subject to dynamic changes in response to an injury. Initially, increased levels of angiotensin (Ang) II and des-Arg9-bradykinin (DABK), are necessary for an effective defense. Later, augmented angiotensin converting enzyme (ACE) 2 activity supposedly helps to attenuate inflammation. Appropriate ACE2 activity might be decisive in preventing immune-induced damage and ensuring tissue repair. ACE2 has been identified as a common target for different pathogens. Some Coronaviruses, including SARS-CoV-2, also use ACE2 to infiltrate the cells. A number of questions remain unresolved. The importance of ACE2 shedding, associated with the release of soluble ACE2 and ADAM17-mediated activation of tumor necrosis factor-α (TNF-α)-signaling is unclear. The roles of other non-classical RAS-associated molecules, e.g., alamandine, Ang A or Ang 1–9, also deserve attention. In addition, the impact of established RAS-inhibiting drugs on the pulmonary RAS is to be elucidated. The unfavorable prognosis of ARDS and the lack of effective treatment urge the search for novel therapeutic strategies. In the context of the ongoing SARS-CoV-2 pandemic and considering the involvement of humoral disbalance in the pathogenesis of ARDS, targeting the renin–angiotensin system and reducing the pathogen’s cell entry could be a promising therapeutic strategy in the struggle against COVID-19.
Highlights
Acute respiratory distress syndrome (ARDS) is defined as an acute, diffuse, inflammatory lung injury, leading to increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue [1]
Ang II-induced shedding of ACE2 is associated with the activation of the ADAM17-mediated pathway [52,54], resulting in enhanced intracellular tumor necrosis factor-α (TNF-α)-signaling, which contributes to tissue damage [56,57,97]
Recent data suggesting that the renin–angiotensin system (RAS) might be one of the principal regulatory systems controlling the immune response in acute lung injury open new horizons for further research in several directions
Summary
Acute respiratory distress syndrome (ARDS) is defined as an acute, diffuse, inflammatory lung injury, leading to increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue [1]. The reabsorption of alveolar and interstitial fluid is associated with the proliferation of type II alveolar cells as well as fibroblasts and myofibroblasts producing components of the extracellular matrix These processes can lead either to the restoration of normal pulmonary tissue or to fibrotic remodeling of the lungs [7]. The RAS has been known for over 120 years and has been mostly studied in relation to blood pressure regulation and cardiovascular disorders [12,13,14,15] In addition to their hemodynamic effects, components of the RAS act in various organs and systems as signaling molecules modulating inflammation, oxidative stress, cell proliferation, tissue remodeling, and apoptotic or necrotic cell death [15,16,17,18,19]. The RAS is closely related to the kinin–kalikrein system, regulating vascular tone and permeability, since ACE and ACE2 participate in the inactivation of bradykinin and des-Arg9-bradykinin (DABK), respectively [26,27]
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