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bioRxiv · 10.64898/2025.12.21.695829

Monocrotaline treatment of the rat predisposes to altered lipopolysaccharide-induced lung responses.

DeBellis, D.·Penn, T.·Cowell, E.·Roach, M. J.·Kris, L. P.·McEvoy-may, J.·Bihari, S.·dixon, d.·Carr, J. M.
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Abstract

There is a need to understand pathogen driven lung disease and the rat is a laboratory model, widely used to study acute lung injury (ALI). Here the monocrotaline (MCT) rat has been investigated as a model of an inflammatory lung with developing pulmonary hypertension (PH) on which an ALI is superimposed. 14 days following a single systemic dose of MCT, the lung is functionally normal, but stimulation with lipopolysaccharide (LPS) results in an altered response. The MCT/LPS lung is morphologically similar to LPS alone, with respiratory mechanics showing increased elastance, reduced compliance and increased tissue resistance. Bronchioalveolar lavage (BAL) fluid demonstrated a cellular infiltrate, with large macrophage-like cells, increased secreted angiotensin converting enzyme-2 (ACE2) and total protein. The lung transcriptome is pushed towards a pro-inflammatory M1 phenotype, (interferon (IFN)-{Upsilon}, interleukin 6 (IL6), CD68 and CD80) compared to LPS alone. Additionally, the MCT/LPS lung has gene transcription signatures for enhanced cell death and DNA damage responses, higher levels of multiple complement components, dysregulation of the renin-angiotensin pathway with reduced ACE2 and increased AGTR1, increased factors such as Erythroferrone that would increase iron levels, and increased fibrinogen and A2M, that would promote thrombosis. Thus, the MCT-treated rat represents an animal with no overt clinical distinction but following LPS stimulation elicits an exacerbated pathogenic lung response. The MCT-treated rat is a simple model that might be beneficial for understanding an M1 lung pathology with activated complement, low ACE2, high iron, and a propensity to clot in the context of developing cardiovascular disease.

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DeBellis, D., Penn, T., Cowell, E., Roach, M. J., Kris, L. P., McEvoy-may, J., Bihari, S., dixon, d., Carr, J. M.. 2025-12-23. Monocrotaline treatment of the rat predisposes to altered lipopolysaccharide-induced lung responses.. https://doi.org/10.64898/2025.12.21.695829

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