The COVID-19 pandemic has covered more than 200 countries and regions around the world since its outbreak in January 2020. To date, the SARS-CoV-2 virus has caused> 1.2 million deaths. The mortality rate of COVID-19 is closely concerned with the clinical symptoms of the patients from mild-to-severe disease. Notably, in its most severe form, COVID-19 leads to life-threatening pneumonia and acute respiratory distress syndrome (ARDS), which is mostly accompanied by a hyperactive immune response called “cytokine storm” and has high death rates from 40 to 50%. 1 To elucidate the mechanisms of COVID-19 immunity and pathogenesis, researchers have developed several SARS-CoV-2 mouse models using transgenic mouse lines expressing hACE2 by the nasal inoculation of SARS-CoV-2. 2, 3 However, these models showed mild-to-moderate interstitial pneumonia with mononuclear cell infiltration, 2, 3 the pathological features of SARS-CoV-2-induced ARDS in humans, such as the disruption of lung tissues with apparent cell death, neutrophil infiltration, proteinaceous debris, hemorrhage, thrombi, and hyaline membranes-like changes, were rarely found in nasal inoculation of SARS-CoV-2 mouse model. 2, 3 Thus, these models failed to recapitulate the acute and severe form of lung injury, especially, its progression to ARDS. Therefore, the establishment of laboratory animal models for ARDS is important to support the studies for COVID-19 progression and treatment evaluation. To establish the mouse model for SARS-CoV-2-induced ARDS, we infected the humanized hACE2-KI mice with C57BL/6 background by intratracheal instillation of SARS-CoV-2 (40 μl, 107 PFU/ml), as demonstrated in Fig. 1 a and in Supplementary Materials. The transgenic hACE2 mice with C57BL/6 background were provided by the National Institutes for Food and Drug Control in China. 2, 4 The studies were performed in the ABSL-4 facility of Kunming National High-level Biosafety Primate Research Center and were reviewed and approved by the Institutional Animal Care and Use Committee of Institute. The lung tissues from the infected mice were collected on 6h, 1 day, 2 days, 3 days, and 5 days post inoculation of SARS-CoV-2 and were investigated for pathological changes. Grossly, lungs from the infected mice got the appearance of the bigger size, with the bilateral congestion and edema, and patches of dark-colored hemorrhage (Fig. 1 b). Furthermore, the lung tissues showed an increase of basophilia and the reduction of airway spaces by the observation with hematoxylin and eosin (H&E) stain under light microscopy (Fig. 1 c, d), which may result from the diffuse heavy inflammatory infiltrates in the lung tissues. Notably, this inflammation is often characterized by the disruption of lung tissues, with the disappearance of recognizable architecture (Fig. 1 d). The dead cells were mostly seen in the background of the inflammatory cell infiltrates and were positively stained by using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) technique (Fig. 1 e). The apparent cell death can be found as early as 6 h post inoculation of SARS-CoV-2. Inflammatory cell exudates were characterized by neutrophilic infiltration at the early stage. As shown in Fig. 1 f, apparent neutrophils can be found in the alveolar or the interstitial space, with more than 60% of lung tissues consolidated at 6h post inoculation of SARS-CoV-2 (Fig. 1 f). Neutrophils were stained positive for Ly6G (Fig. 1 g). Neutrophils remained predominant cell infiltration 24 h and 48 h post inoculation. The scattered monocytes/macrophages or lymphocytes gradually increased at 3 and 5 days …