Pharmacological blockade of infection chronification modulates oxy-inflammation and prevents the activation of stress-induced premature senescence markers in schistosomiasis.

Chronic inflammation, oxidative stress, and DNA damage are observed in schistosomiasis and premature aging. However, the potential of these events to trigger stress-induced premature senescence (SIPS) throughout schistosomiasis progression remains overlooked, especially in response to the first-line pharmacological treatment. Thus, we investigated the relationship between oxidative stress and SIPS sentinel markers in untreated Schistosoma mansoni-infected mice and those receiving praziquantel (Pz)-based reference treatment. Swiss mice were randomized into 5 groups: uninfected (followed by 60- and 180-days post-infection), acutely (60 days) and chronically (180 days) infected untreated, and infected treated with Pz followed until 180 days. Our results indicated that infection chronification was accompanied by the worsening of hepatic granulomatous inflammation, increased number of granulomas, IL-4, TGF-β, reactive oxygen species (ROS) levels, fibrosis, hepatocytes DNA damage, upregulation in SA-β-gal activity, p16 and p21 gene expression, and hepatocytes proliferation down-regulation in the absence of telomeric shortening. These abnormalities were blocked by Pz treatment, which prevented infection chronification and the decline in hepatocytes proliferative potential, stimulating granulomatous inflammation resolution. Taken together, our findings provide the evidence that progressive fibrosis, sustained production of high ROS levels, marked DNA damage and decline in p16 and p21 expression are associated with hepatocytes replication attenuation in the chronic phase of S. mansoni infection. Thus, pharmacological blockade of infection and granulomatous inflammation is essential to prevent these premature senescence markers associated with hepatocytes replicative disorders, stimulating liver regeneration in schistosomiasis mansoni.