Growth hormone-releasing hormone receptor antagonist MIA-602 attenuates cardiopulmonary injury induced by BSL-2 rVSV-SARS-CoV-2 in hACE2 mice.
Jose M Condor CapchaAli KamiarEmely RobletoAli G SaadTengjiao CuiAmanda WongJason VillanoWilliam ZhongAndrew S PekoszEdgar MedinaRenzhi CaiWei ShaMark J RanekKeith A WebsterAndrew V SchallyRobert M JacksonLina A ShehadehPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
COVID-19 pneumonia causes acute lung injury and acute respiratory distress syndrome (ALI/ARDS) characterized by early pulmonary endothelial and epithelial injuries with altered pulmonary diffusing capacity and obstructive or restrictive physiology. Growth hormone-releasing hormone receptor (GHRH-R) is expressed in the lung and heart. GHRH-R antagonist, MIA-602, has been reported to modulate immune responses to bleomycin lung injury and inflammation in granulomatous sarcoidosis. We hypothesized that MIA-602 would attenuate rVSV-SARS-CoV-2-induced pulmonary dysfunction and heart injury in a BSL-2 mouse model. Male and female K18-h ACE2 tg mice were inoculated with SARS-CoV-2/USA-WA1/2020, BSL-2-compliant recombinant VSV-eGFP-SARS-CoV-2-Spike (rVSV-SARS-CoV-2), or PBS, and lung viral load, weight loss, histopathology, and gene expression were compared. K18-h ACE2 tg mice infected with rVSV-SARS-CoV-2 were treated daily with subcutaneous MIA-602 or vehicle and conscious, unrestrained plethysmography performed on days 0, 3, and 5 (n = 7 to 8). Five days after infection mice were killed, and blood and tissues collected for histopathology and protein/gene expression. Both native SARS-CoV-2 and rVSV-SARS-CoV-2 presented similar patterns of weight loss, infectivity (~60%), and histopathologic changes. Daily treatment with MIA-602 conferred weight recovery, reduced lung perivascular inflammation/pneumonia, and decreased lung/heart ICAM-1 expression compared to vehicle. MIA-602 rescued altered respiratory rate, increased expiratory parameters (Te, PEF, EEP), and normalized airflow parameters (Penh and Rpef) compared to vehicle, consistent with decreased airway inflammation. RNASeq followed by protein analysis revealed heightened levels of inflammation and end-stage necroptosis markers, including ZBP1 and pMLKL induced by rVSV-SARS-CoV-2, that were normalized by MIA-602 treatment, consistent with an anti-inflammatory and pro-survival mechanism of action in this preclinical model of COVID-19 pneumonia.
Keyphrases
- sars cov
- gene expression
- respiratory syndrome coronavirus
- weight loss
- acute respiratory distress syndrome
- growth hormone
- oxidative stress
- pulmonary hypertension
- immune response
- heart failure
- mechanical ventilation
- mouse model
- bariatric surgery
- high fat diet induced
- anti inflammatory
- physical activity
- stem cells
- extracorporeal membrane oxygenation
- dna methylation
- binding protein
- mesenchymal stem cells
- lps induced
- lipopolysaccharide induced
- systemic sclerosis
- adipose tissue
- insulin resistance
- gastric bypass
- metabolic syndrome
- roux en y gastric bypass
- high glucose
- toll like receptor
- weight gain
- endothelial cells
- cell therapy
- pulmonary fibrosis
- combination therapy
- respiratory failure
- newly diagnosed
- dendritic cells
- angiotensin ii
- data analysis
- replacement therapy
- community acquired pneumonia