Chemotherapy-induced pulmonary hypertension: Role of alkylating agents

Abstract

Rationale: Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. Methods: We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal species (mouse, rat and rabbit). Results: Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (CP, 43.2%). In experimental models, CP exposure induced PH in the 3 different animal species. In rats, the severity of PH and vascular remodeling was sex-dependent (females more susceptible than males), time-dependent, and dose-dependent. We also demonstrate in rats that amifostine pre-treatment improved survival and ameliorated PH severity after CP exposure. Rabbits exposed to CP displayed features of congestive lungs and venular involvement, mimicking human PVOD. Interestingly, CP-exposure was associated with recognized triggers of PAH: raise in pulmonary serotonin content, overproduction of endothelin-1, or vascular inflammation among others. Conclusions: Clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon but severe pulmonary vascular complication of alkylating agents.