Revisiting the monocrotaline-treated rat as a model of inflammatory lung disease: COVID-19 and future pandemic threats?

The COVID-19 pandemic posed a challenge for clinical management of a new lung disease that was characterized by inflammation, endothelial cell dysfunction, and thrombosis, which occur after the replication phase of infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are many laboratory models of active SARS-CoV-2 infection in mice, reflecting an acute lung injury in an otherwise healthy animal, but there is a lack of accurate animal models of the postviral inflammatory phase of the COVID-19 lung reflecting severe disease. The monocrotaline (MCT)–treated rat is a widely used laboratory model of pulmonary hypertension (PH). Not often discussed, however, are the observed changes in inflammation, edema, fibrosis, and microthrombosis in the lung prior to PH. At the cellular level, there is loss of pneumocytes and endotheliopathy, and at the molecular level the MCT rat lung is characterized by a pro-inflammatory cytokine profile, namely elevated interleukin 6, transforming growth factor β and tumor necrosis factor, M1 macrophage phenotype, and dysregulation of the angiotensin converting enzyme (ACE)/ACE2 balance. The systems-level pathophysiology of the MCT-treated rat includes progressive cardiopulmonary dysfunction. The MCT-treated rat clearly differs from the COVID-19 lung in terms of the triggers for pathology, but there are many parallels apparent in both the MCT-treated rat and the COVID-19 lung. The MCT-treated rat lung as a model of the COVID-19 lung may provide an in-depth understanding of the factors that drive the lung to more severe pathology, treatments that benefit lung recovery, or the factors that prove a useful research platform for future emerging respiratory threats of similar pathology.