A molecular single-cell lung atlas of lethal COVID-19.

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection1,2, but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19. The lungs from individuals with COVID-19 were highly inflamed, with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but had impaired T cell responses. Monocyte/macrophage-derived interleukin-1ß and epithelial cell-derived interleukin-6 were unique features of SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. Alveolar type 2 cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type 1 cells, resulting in impaired lung regeneration. Furthermore, we identified expansion of recently described CTHRC1+ pathological fibroblasts3 contributing to rapidly ensuing pulmonary fibrosis in COVID-19. Inference of protein activity and ligand-receptor interactions identified putative drug targets to disrupt deleterious circuits. This atlas enables the dissection of lethal COVID-19, may inform our understanding of long-term complications of COVID-19 survivors, and provides an important resource for therapeutic development.

Mitigation of radiation myelopathy and reduction of microglial infiltration by Ramipril, ACE inhibitor.

STUDY DESIGN: Experimental study. OBJECTIVES: To evaluate the efficacy of Angiotensin-converting enzyme inhibitor Ramipril, as a mitigator of radiation-induced spinal cord injury. SETTING: Stony Brook University, Stony Brook, NY, USA. METHODS: Total of 22 rats were irradiated with single doses of 23.6-33 Gy at the C4-T2 spinal levels. After irradiation, the rats were randomized to the radiation only control group and the Ramipril-treated (radiation + Ramipril) experimental group. Ramipril 1.5 mg/kg/day was given in the drinking water starting 1 week after radiation through the study duration. RESULTS: All the rats irradiated with 28.5-33 Gy became paralyzed at 125 ± 4 days, whereas no rats became paralyzed after 23.6 Gy. The time to develop paralysis was delayed to 135 ± 4 days in Ramipril-treated group (P < 0.001). H&E and LFB showed microscopic structural restoration and remyelination with Ramipril treatment. VEGF expression was increased in the irradiated spinal cord, and the number of VEGF-positive cells was significantly decreased by Ramipril treatment (P < 0.001). Immunohistochemical stain with Iba-1 showed increased microglial infiltration in the irradiated spinal cords. The number of Iba-1-positive microglia was significantly reduced by Ramipril treatment (P < 0.05). CONCLUSION: Ramipril reduced the rate of paralysis even at the paralysis-inducing radiation doses. It also significantly delayed the onset of paralysis. Neuroinflammation and endothelial cell damage may be the key mediators of radiation injury. Ramipril can be readily translatable to clinical application as a mitigatory of radiotherapeutic toxicity.