Physiological responses to cisplatin using a mouse hypersensitivity model

Abstract

Background: The physiological mechanisms underlying the development of respiratory hypersensitivity to cisplatin (CDDP) are not well-understood. It has been suggested that these reactions are likely the result of type I hypersensitivity, but other explanations are plausible and the potential for CDDP to induce type I hypersensitivity responses has not been directly evaluated in an animal model.

Objectives and Methods: To investigate CDDP hypersensitivity, mice were topically sensitized through application of CDDP before being challenged by oropharyngeal aspiration (OPA) with CDDP. Before and immediately after OPA challenge, pulmonary responses were assessed using whole body plethysmography (WBP).

Results: CDDP did not induce an immediate response or alter the respiratory rate in sensitized mice. Two days later, baseline enhanced pause (Penh) values were significantly elevated (p < 0.05) in mice challenged with CDDP. When challenged with methacholine (Mch) aerosol, Penh values were significantly elevated (p < 0.05) in sensitized mice and respiratory rate was reduced (p < 0.05). Lymph node cell counts and immunoglobulin E levels also indicated successful sensitization to CDDP. Irrespective of the sensitization state of the mice, the number of neutrophils increased significantly in bronchoalveolar lavage fluid (BALF) following CDDP challenge. BALF from sensitized mice also contained 2.46 (±0.8) × 10⁴ eosinophils compared to less than 0.48 (±0.2) × 10⁴ cells in non-sensitized mice (p < 0.05).

Conclusions: The results from this study indicate that dermal exposure to CDDP induces immunological changes consistent with type I hypersensitivity and that a single respiratory challenge is enough to trigger pulmonary responses in dermally sensitized mice. These data provide previously unknown insights into the mechanisms of CDDP hypersensitivity.

Keywords:

• Platinum
• cisplatin
• occupational asthma
• respiratory hypersensitivity
• whole-body plethysmography
• pulmonary hyperresponsiveness

Acknowledgments

The authors thank C. Copeland, L. Copeland, D. Andrews, and J. Richards for their expert technical assistance. We also thank Drs. A. Farraj, R. Koethe, and M. J. Selgrade for their thoughtful and critical review of this work.

Disclosure statement

This article has been reviewed by the U.S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency or of the US Federal Government, nor does the mention of trade names or commercial products constitute endorsement or recommendations for use of those products. No potential conflict of interest was reported by the author(s).