Asthma is a frequent respiratory disease characterized by bronchial hyperresponsiveness, inflammation and remodeling. Bronchial remodeling corresponds to structural modification of the bronchial wall. Increase of smooth muscle mass is a crucial feature of such a remodeling in asthma. Indeed, it correlates with the decrease in lung function and bronchial thermoplasty, which is supposed to decrease BSM mass, was associated with a decrease in exacerbation rate. The mechanisms of such an increased BSM mass are complex and remain controversial. However, increased proliferation of asthmatic BSM cells has been proposed and largely documented both in vitro and in vivo. We previously demonstrated that such an increased BSM cell proliferation involved an increased mitochondrial biogenesis and mitochondrial mass through the increase of PGC-1α and Tfam expression. Major tumor suppressor protein p53 is a key cell regulator involved in cell proliferation and has also been implicated in mitochondrial biogenesis. However, the role of p53 in BSM cell proliferation and mitochondrial biogenesis has not been investigated so far. We thus hypothesized that, p53 can modulate BSM cell mitochondrial biogenesis and proliferation and that this modulation is disrupted in asthmatic cells.

Using shRNA lentivirus targeting p53, we assessed the role of p53 in both asthmatic and control BSM cells proliferation using both BrdU and cell counting. We analyzed the effect of the down-regulation of p53 protein on the regulation of p21, Bax, TFAM and PGC-1α mRNA. Finally, we assessed the expression of p53 in vitro using flow cytometry and western blot but also ex vivo using laser microdissection and RT-PCR.

We found that, p53 is unable to inhibit the transcription of Tfam and PGC1α in asthmatic BSM. As a consequence, p53 cannot slow down the increased mitochondrial biogenesis and the subsequent increased proliferation of asthmatic BSM cells. We also found that p53 expression was increased in asthmatic BSM, which was related with a loss of Mdm2 activation by p53.

In conclusion, this work highlights p53 as a new potential therapeutic target against BSM remodeling in asthma.