A novel protective role for nSMase2/SMPD3 in lung emphysema

Emphysema is a devastating disease mainly caused by smoking; it affects several million patients in the US alone. Smoking triggers some mechanisms which ultimately result in lung inflammation and breathing problems observed in patients with emphysema; these mechanisms are still poorly understood. It has been described that the ceramide‐generating nSMase2/SMPD3 enzyme was activated by cigarette smoke in the lung of mice. As expected, cigarette smoke‐induced nSMase2 activation was followed by an increase in ceramide production. The authors speculated that emphysema was caused by nSMase2 activation and the subsequent increase in ceramide content because ceramide is a well characterized signaling sphingolipid. Our data with nSMase2‐deficient mice challenged this hypothesis. Indeed, we found that nSMase2‐deficient mice developed spontaneously a lung disorder similar to emphysema. We also found a strong sex effect associated with the disorder, males were more affected than females. We hypothesize that nSMase2 play a critical role in lung maintenance and repair. According to our hypothesis, nSMase2 activation in the lung of smokers is a protective mechanism in response to the toxic effect of cigarette smoke.