Aspergillus fumigatus-induced early inflammatory response in pulmonary microvascular endothelial cells: Role of p38 MAPK and inhibition by silibinin.

Human invasive pulmonary aspergillosis (IPA) is a serious infectious disease mainly caused by Aspergillus fumigatus (A. fumigatus). Pulmonary microvascular endothelial cells (PMVECs) are important ones in the human lung tissue. However, it remains unclear about the role of PMVECs in IPA. In the present study, we cocultured PMVECs with A. fumigatus. We observed that A. fumigatus induced dose- and time-dependent increases of interleukin 6 (IL-6), interleukin 1β (IL-1β) and intercellular adhesion molecule 1 (ICAM-1) concentration in the cultures. Significant increases in IL-6, IL-1β, E-selectin, and ICAM-1 mRNA expression were also observed in the cultures treated with A. fumigatus. While preincubation with SB203580 (10μM) did not cause significant changes in IL-6, IL-1β and ICAM-1 concentration in the cocultures, significant IL-6, IL-1β and ICAM-1 concentration decreases were observed in the cocultures preincubated with SB203580 (20μM). Neither SP600125 (10-20μM) nor PD98059 (10-20μM) caused significant changes in IL-6, IL-1β and ICAM-1 concentration in the cocultures. PCR results also showed that SB203580 (20μM) (neither SP600125 (20μM) nor PD98059 (20μM)) preincubation significantly decreased IL-6, IL-1β, E-selectin and ICAM-1 mRNA expression in the cocultures. In addition, significant p38 MAPK phosphorylation increase was observed in the PMVECs cultures treated with A. fumigatus. Furthermore, silibinin pre-treatment and post-treatment were observed to significantly down-regulate mRNA and protein expression of proinflammatory factors and adhesion molecules in the cocultures. Finally, we observed that silibinin significantly inhibited A. fumigatus-induced p38 MAPK activation in PMVECs. Our results indicated that PMVECs might participate in IPA early inflammation which is mediated by p38 MAPK. Silibinin may inhibit A. fumigatus-induced inflammation in PMVECs through p38 MAPK.