The main clinical feature of ARDS patients is the progressive deterioration of lung function leading to progressive hypoxemia. ARDS can be induced by different causes such as ZnCl2 aspiration, sepsis, trauma, acute pancreatitis, or pneumonias following virus infections such as SARS-CoVs or human influenza virus. ACE insertion/deletion polymorphisms correlated with severity of ARDS in humans, suggesting that the RAS could have a role in ARDS [44]. In animal models, ACE2 protected from acute lung by inhibiting Ang II/AT1R activity [15], for this reason the use of recombinant ACE2 in ARDS has been proposed and pursued [134]. Clinical trials with recombinant human ACE2 started in healthy volunteers in 2009 (ClinicalTrials.gov number, NCT00886353 [178]), then it was tested in ARDS (ClinicalTrials.gov number, NCT01597635 [134]), PAH (ClinicalTrials.gov number, NCT01884051 [108]) and finally in COVID-19 patients (ClinicalTrials.gov number, NCT04287686). Despite its safe use, no conclusive evidence in support of its use in these diseases was reported.