Protective Effect of Calpain Inhibition During Cold Ischemia on Ischemia-reperfusion Injury After Lung Transplantation

by Selleckchem | Jun 06 2023

Background: Necroptosis, one of the types of regulated necrosis, causes ischemia-reperfusion (IR) lung injury. N-acetyl-leucyl-leucyl-norleucinal (ALLN), a calpain inhibitor, is known to attenuate necroptosis and apoptosis, and the purpose of this study was to evaluate the protective effect of ALLN during cold ischemia against IR injury in a rat lung transplant model.

Methods: Male Lewis rats (250-350 g) were divided into 3 groups: sham group (n = 4), nontransplantation; control group (n = 8), transplantation with IR lung injury; and ALLN group (n = 8), transplantation with IR lung injury/ALLN. Rats in the sham group underwent a simple thoracotomy, and the remaining 2 groups of rats underwent an orthotopic left lung transplant. Cold ischemic time was 15 h. After 2 h of reperfusion, physiological function, inflammatory cytokine expression, pathway activation, and the degrees of necroptosis and apoptosis were evaluated.

Results: Lung gas exchange (PaO 2 /FiO 2 ) was significantly better, and pulmonary edema was significantly improved in the ALLN group compared with the control group ( P = 0.0009, P = 0.0014). Plasma expression of interleukin-1β was significantly lower in the ALLN group than in the control group ( P = 0.0313). The proportion of necroptotic and apoptotic cells was significantly lower in the ALLN group than in the control group ( P = 0.0009), whereas the proportion of apoptotic cells remained unchanged ( P = 0.372); therefore, the calpain inhibitor was thought to suppress necroptosis.

Conclusion: The administration of ALLN during cold ischemia appears to improve IR lung injury in a lung transplant animal model via the inhibition of necroptosis.

Comments:

In this study, the protective effect of the calpain inhibitor N-acetyl-leucyl-leucyl-norleucinal (ALLN) against ischemia-reperfusion (IR) lung injury was evaluated in a rat lung transplant model. Male Lewis rats were divided into three groups, including a sham group, a control group, and an ALLN group. The control and ALLN groups underwent orthotopic left lung transplant with cold ischemic time of 15 hours, while the sham group underwent simple thoracotomy. After 2 hours of reperfusion, physiological function, inflammatory cytokine expression, pathway activation, and the degrees of necroptosis and apoptosis were evaluated.

The results showed that the administration of ALLN during cold ischemia significantly improved lung gas exchange and pulmonary edema compared to the control group. Plasma expression of interleukin-1β was also significantly lower in the ALLN group than in the control group. Additionally, the proportion of necroptotic and apoptotic cells was significantly lower in the ALLN group than in the control group, while the proportion of apoptotic cells remained unchanged. Thus, the calpain inhibitor was thought to suppress necroptosis.

In conclusion, the results suggest that the administration of ALLN during cold ischemia could improve IR lung injury in a lung transplant animal model by inhibiting necroptosis.