Acetylsalicylic acid and dihydroartemisinin combined therapy on experimental malaria-associated acute lung injury: analysis of lung function and the inflammatory process

• Published in: Malaria journal Vol. 23; no. 1; pp. 285 - 14
• Main Authors: de Oliveira, Helena D'Anunciação, Batista, Camila Nunes, Lima, Maiara Nascimento, Lima, Ana Carolina, Dos Passos, Beatriz Amanda Barbosa Rangel, Freitas, Rodrigo Jose Rocha Xavier, Silva, Johnatas Dutra, Xisto, Debora Gonçalves, Rangel-Ferreira, Marcos Vinícius, Pelajo, Marcelo, Rocco, Patricia Rieken Macedo, Ribeiro-Gomes, Flávia Lima, de Castro Faria-Neto, Hugo Caire, Maron-Gutierrez, Tatiana
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 19.09.2024; BMC
• Subjects: Acetylsalicylic acid; Acute Lung Injury - drug therapy; Acute Lung Injury - parasitology; Acute respiratory distress syndrome; Analysis; Animals; Antimalarials - pharmacology; Artemisinins - pharmacology; Aspirin; Aspirin - administration & dosage; Aspirin - pharmacology; Dihydroartemisinin; Disease Models, Animal; Dosage and administration; Drug therapy; Drug Therapy, Combination; Health aspects; Inflammation; Lung - drug effects; Lung - pathology; Lung diseases; Lung edema; Malaria; Malaria - complications; Malaria - drug therapy; Male; Mice; Mice, Inbred C57BL; Patient outcomes; Plasmodium berghei - drug effects; Prevention; Respiratory Function Tests; Risk factors; Salicylates; Brazil; Acute respiratory distress syndrome; Dihydroartemisinin; Acetylsalicylic acid; Malaria; Lung edema
• ISSN: 1475-2875; 1475-2875
• DOI: 10.1186/s12936-024-05017-7

Severe malaria can cause respiratory symptoms, which may lead to malaria-acute lung injury (MA-ALI) due to inflammation and damage to the blood-gas barrier. Patients with severe malaria also often present thrombocytopenia, and the use of acetylsalicylic acid (ASA), a commonly used non-steroidal anti-inflammatory drug with immunomodulatory and antiplatelet effects, may pose a risk in regions where malaria is endemic. Thus, this study aimed to investigate the systemic impact of ASA and dihydroartemisinin (DHA) on ALI induced in mice by Plasmodium berghei NK65 (PbNK65). C57BL/6 mice were randomly divided into control (C) and PbNK65 infected groups and were inoculated with uninfected or 10 infected erythrocytes, respectively. Then, the animals were treated with DHA (3 mg/kg) or vehicle (DMSO) at the 8-day post-infection (dpi) for 7 days and with ASA (100 mg/kg, single dose), and analyses were performed at 9 or 15 dpi. Lung mechanics were performed, and lungs were collected for oedema evaluation and histological analyses. PbNK65 infection led to lung oedema, as well as increased lung static elastance (Est, L), resistive (ΔP1, L) and viscoelastic (ΔP2, L) pressures, percentage of mononuclear cells, inflammatory infiltrate, hemorrhage, alveolar oedema, and alveolar thickening septum at 9 dpi. Mice that received DHA or DHA + ASA had an increase in Est, L, and CD36 expression on inflammatory monocytes and higher protein content on bronchoalveolar fluid (BALF). However, only the DHA-treated group presented a percentage of inflammatory monocytes similar to the control group and a decrease in ΔP1, L and ΔP2, L compared to Pb + DMSO. Also, combined treatment with DHA + ASA led to an impairment in diffuse alveolar damage score and lung function at 9 dpi. Therapy with ASA maintained lung morpho-functional impairment triggered by PbNK65 infection, leading to a large influx of inflammatory monocytes to the lung tissue. Based on its deleterious effects in experimental MA-ALI, ASA administration or its treatment maintenance might be carefully reconsidered and further investigated in human malaria cases.