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Background <p>Methotrexate (MTX) is a cornerstone chemotherapeutic and immunosuppressive agent widely used in the treatment of hematological malignancies, including acute lymphoblastic leukemia, Burkitt lymphoma, and primary central nervous system lymphoma. Despite its clinical efficacy, MTX use may be limited by pulmonary toxicity, a rare but potentially life-threatening adverse effect. Previous studies suggest that MTX-induced lung injury is associated with inflammatory responses, endothelial activation, and oxidative stress–related mechanisms reported in the literature. These processes may contribute to structural lung damage and impaired pulmonary integrity. Pregabalin (PREG), a structural analog of γ-aminobutyric acid, has been reported to exhibit anti-inflammatory, and cytoprotective properties in several experimental models. In addition, previous experimental studies suggest that PREG may attenuate endothelial activation and inflammatory mediator release. Therefore, the present study aimed to investigate the potential protective effects of PREG against MTX-induced pulmonary injury, focusing on histopathological and immunohistochemical alterations.</p> Methods <p>Adult male Wistar rats were randomly allocated into four experimental groups: Control, MTX, MTX + PREG, and PREG. Pulmonary injury was induced by a single intraperitoneal administration of MTX (20&#xa0;mg/kg). PREG (30&#xa0;mg/kg/day) was administered orally for seven consecutive days. At the end of the experimental period, lung tissues were collected for histopathological examination using hematoxylin and eosin staining. Immunohistochemical analyses were performed to evaluate the expression of cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Immunoreactivity was assessed semi-quantitatively across the experimental groups.</p> Results <p>MTX exposure resulted in marked pulmonary injury characterized by pronounced alveolar septal thickening, interstitial and alveolar edema, hemorrhage, and extensive inflammatory infiltration. These histopathological changes were accompanied by a significant increase in COX-2, IL-6, and VCAM-1 immunoreactivity, indicating enhanced inflammatory and endothelial activation within lung tissue. In contrast, PREG co-treatment significantly attenuated MTX-induced lung injury, as evidenced by lower histopathological injury scores and reduced numbers of immunopositive cells for all markers. The PREG-only group exhibited preserved pulmonary architecture without detectable pathological alterations.</p> Conclusion <p>PREG significantly attenuated MTX-induced pulmonary injury in this experimental model, as demonstrated by improved histopathological findings and reduced expression of inflammatory and endothelial activation markers, including COX-2, IL-6, and VCAM-1. These results provide tissue-level evidence supporting the potential protective effects of PREG against MTX-associated lung injury. However, oxidative stress parameters, functional pulmonary assessments, and intracellular signaling pathways were not directly evaluated in the present study. Therefore, the findings should be interpreted as morphological and hypothesis-generating evidence. Further investigations incorporating molecular, biochemical, and functional analyses are required to clarify the underlying mechanisms and to determine the translational relevance of these observations.</p>

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Pregabalin mitigates methotrexate-induced pulmonary injury via suppression of inflammatory and endothelial activation mechanisms: a histopathological and immunohistochemical approach

  • 期刊论文

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  • 发表日期：

    2026年5月25日

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  • Sibel Kabukcu Hacioglu,
  • Ozlem Ozmen,
  • Halil Asci

摘要

Background

Methotrexate (MTX) is a cornerstone chemotherapeutic and immunosuppressive agent widely used in the treatment of hematological malignancies, including acute lymphoblastic leukemia, Burkitt lymphoma, and primary central nervous system lymphoma. Despite its clinical efficacy, MTX use may be limited by pulmonary toxicity, a rare but potentially life-threatening adverse effect. Previous studies suggest that MTX-induced lung injury is associated with inflammatory responses, endothelial activation, and oxidative stress–related mechanisms reported in the literature. These processes may contribute to structural lung damage and impaired pulmonary integrity. Pregabalin (PREG), a structural analog of γ-aminobutyric acid, has been reported to exhibit anti-inflammatory, and cytoprotective properties in several experimental models. In addition, previous experimental studies suggest that PREG may attenuate endothelial activation and inflammatory mediator release. Therefore, the present study aimed to investigate the potential protective effects of PREG against MTX-induced pulmonary injury, focusing on histopathological and immunohistochemical alterations.

Methods

Adult male Wistar rats were randomly allocated into four experimental groups: Control, MTX, MTX + PREG, and PREG. Pulmonary injury was induced by a single intraperitoneal administration of MTX (20 mg/kg). PREG (30 mg/kg/day) was administered orally for seven consecutive days. At the end of the experimental period, lung tissues were collected for histopathological examination using hematoxylin and eosin staining. Immunohistochemical analyses were performed to evaluate the expression of cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Immunoreactivity was assessed semi-quantitatively across the experimental groups.

Results

MTX exposure resulted in marked pulmonary injury characterized by pronounced alveolar septal thickening, interstitial and alveolar edema, hemorrhage, and extensive inflammatory infiltration. These histopathological changes were accompanied by a significant increase in COX-2, IL-6, and VCAM-1 immunoreactivity, indicating enhanced inflammatory and endothelial activation within lung tissue. In contrast, PREG co-treatment significantly attenuated MTX-induced lung injury, as evidenced by lower histopathological injury scores and reduced numbers of immunopositive cells for all markers. The PREG-only group exhibited preserved pulmonary architecture without detectable pathological alterations.

Conclusion

PREG significantly attenuated MTX-induced pulmonary injury in this experimental model, as demonstrated by improved histopathological findings and reduced expression of inflammatory and endothelial activation markers, including COX-2, IL-6, and VCAM-1. These results provide tissue-level evidence supporting the potential protective effects of PREG against MTX-associated lung injury. However, oxidative stress parameters, functional pulmonary assessments, and intracellular signaling pathways were not directly evaluated in the present study. Therefore, the findings should be interpreted as morphological and hypothesis-generating evidence. Further investigations incorporating molecular, biochemical, and functional analyses are required to clarify the underlying mechanisms and to determine the translational relevance of these observations.