Therapeutic Effects of Pentoxifylline on Invasive Pulmonary Aspergillosis in Immunosuppressed Mice

Background: The most common and severe infection of Aspergillus fumigatus is invasive pulmonary aspergillosis (IPA), which is usually seen in immunocompromised patients. Neutropenia is the primary risk factor implicated in IPA; however, IPA also occurs in patients without neutropenia, namely, those who are immunosuppressed owing to long-term corticosteroid use. With IPA-associated mortality as high as 51-79%, novel and effective treatment strategies are urgently needed. Pentoxifylline (PTX) has been shown to competitively inhibit the family 18 chitinases in fungi, which may be an new antifungal therapy. Hence, the aim of our study was to compare neutropenic and non-neutropenic IPA mouse models, and to evaluate the effect of PTX on IPA in immunosuppressed mice.

Methods: C57BL/6J mice were pre-treated with cyclophosphamide and hydrocortisone. Neutropenic model IPA mice (CTX-IPA) and non-neutropenic IPA mice (HC-IPA) were established by intranasal administration of Aspergillus fumigatus spore suspension. A subset of each group was injected with PTX post-infection. Among these groups, we compared overall survival, pulmonary fungal burden, lung hispathology, and myeloperoxidase (MPO), interleukin 8 (IL-8), and mammalian chitinase concentration in the bronchoalveolar lavage fluid (BALF).

Results: The survival rate of the HC-IPA group was higher than that of the CTX-IPA group, and pulmonary fungal burden was also lower (p < 0.05). The CTX-IPA group showed infiltration of alveolae and blood vessels by numerous hyphae of A. fumigatus. The HC-IPA group exhibited destruction of bronchi, expansion of alveolar septa, increased macrophages aggregation, significant neutrophil infiltration and a few hyphae in peribronchial areas. After PTX treatment, improvement was observed in survival duration and pulmonary fungal burden in HC-IPA mice. MPO and IL-8 levels were lower in the HC-IPA + PTX group compared to the corresponding levels in the HC-IP group. Chitotriosidase (CHIT1) and Chitinase 3-like 1 (CHI3L1) expression in the HC-IPA group was decreased after PTX treatment (p < 0.05).

Conclusion: PTX was found to exert a therapeutic effect in a non-neutropenic mouse model of IPA, which may lead to the development of novel strategies for IPA treatment.