| Summary: | Paracetamol and nonsteroidal anti-inflammatory drugs are widely used in the management of respiratory viral infections. This study aimed to determine the effects of the most commonly used analgesics (paracetamol, ibuprofen, and diclofenac) on the mRNA expression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry and arachidonic-acid-metabolizing genes in mouse lungs. A total of twenty eight Balb/c mice were divided into four groups and treated separately with vehicle, paracetamol, ibuprofen, and diclofenac in clinically equivalent doses for 14 days. Then, the expressions of SARS-CoV-2 entry, <i>ACE2</i>, <i>TMPRSS2</i>, and <i>Ctsl</i> genes, in addition to the arachidonic-acid-metabolizing <i>cyp450</i>, <i>cox</i>, and <i>alox</i> genes, were analyzed using real-time PCR. Paracetamol increased the expressions of <i>TMPRSS2</i> and <i>Ctsl</i> genes by 8.5 and 5.6 folds, respectively, while ibuprofen and diclofenac significantly decreased the expression of the <i>ACE2</i> gene by more than 2.5 folds. In addition, all tested drugs downregulated (<i>p</i> < 0.05) <i>cox2</i> gene expression, and paracetamol reduced the mRNA levels of <i>cyp4a12</i> and <i>2j5</i>. These molecular alterations in diclofenac and ibuprofen were associated with pathohistological alterations, where both analgesics induced the infiltration of inflammatory cells and airway wall thickening. It is concluded that analgesics such as paracetamol, ibuprofen, and diclofenac alter the expression of SARS-CoV-2 entry and arachidonic-acid-metabolizing genes in mouse lungs.
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