What question did this study set out to answer?

This research aims to evaluate the protective effects of atomoxetine against methotrexate-induced lung damage in rats.

May 2, 2026

Atomoxetine attenuates methotrexate-induced lung injury in rats implicating TLR4/NF-κB and Bax/Bcl-2/caspase-3 signaling cascades: a study based on molecular docking and experimental validation.

Key Points

This research aims to evaluate the protective effects of atomoxetine against methotrexate-induced lung damage in rats.
24 male Wistar albino rats were randomly assigned to four groups: Control, ATOM, MTX, and MTX+ATOM.
Lung injury markers like MDA, GSH, and SOD levels were measured; cytokines IL-10, IL-6, TNF-α, and apoptosis markers Bax and Bcl-2 were assessed using ELISA.
Western blotting assessed TLR4 and MYD88 protein expression, and immunohistochemistry evaluated NF-κB p65 and caspase-3 levels.
MTX administration increased lung MDA, IL-6, TNF-α, and Bax levels, while decreasing GSH, SOD, IL-10, and Bcl-2 levels.
ATOM treatment significantly reversed MTX-induced biochemical and histological abnormalities, restoring normal levels of inflammatory and apoptotic markers.
ATOM mitigated the activation of the TLR4/MYD88/NF-κB p65 and caspase-3 pathways associated with lung injury.

Abstract

Methotrexate (MTX) is frequently used to treat a variety of autoimmune diseases and malignancies, but its use is restricted due to a number of side effects, including lung damage. For the first time, this study attempts to assess the potential protective advantages of atomoxetine (ATOM) against MTX-induced lung damage in rats. MTX was used to cause lung damage. A total of 24 male Wistar albino rats were used in this study. Animals were randomly allocated to four experimental groups of six rats each: (Ⅰ) Control group, (Ⅱ) ATOM group, (Ⅲ) MTX group, and (Ⅳ) MTX+ATOM group. Malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) levels in the lungs were measured. ELISA was used to measure the levels of lung IL-10, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2). NF-κB p65 and caspase-3 were evaluated using immunohistochemistry. Toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MYD88) protein expression levels were assessed using the Western blot technique. A histopathological study of lung tissues was performed. Lung MDA, IL-6, TNF-α, and Bax levels were significantly increased by MTX, while GSH, SOD, IL-10, and Bcl-2 levels were significantly decreased. Additionally, this led to the overexpression of the proteins TLR4 and MYD88. Additionally, the MTX group had higher immunopositivity for both NF-κB p65 and caspase-3. All of the aforementioned biochemical and histological abnormalities were greatly improved with ATOM. ATOM significantly improved MTX-induced pulmonary injury by suppressing TLR4/MYD88/NF-κB p65 and caspase-3-mediated apoptotic signaling pathways.

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