BTP2, a Store-Operated Calcium Channel Inhibitor, Attenuates Lung Ischemia-Reperfusion Injury in Rats

Abstract

Lung ischemia-reperfusion (I/R) injury is a critical complication following a lung transplant, cardiopulmonary bypass, pulmonary embolism, and trauma. Immune cells and their effector functions are involved in the lung I/R injury. Store-operated calcium channels (SOCC) are highly Ca-selective cation channels and have crucial effects on the immune system. It has been indicated that BTP2, a potent SOCC blocker, could inhibit pro-inflammatory cytokine production from immune cells both in vitro and in vivo. Therefore, this study was conducted to investigate the beneficial effects of BTP2 on lung I/R injury in Sprague-Dawley (SD) rats. The left lungs of male SD rats underwent ischemia for 60 min and reperfusion for 2 h. Treated animals received BTP2 4 mg/kg or 10 mg/kg intraperitoneally 30 min before the ischemia. The results revealed that pretreatment with BTP2 markedly attenuated I/R injury-induced pulmonary edema, microvascular protein leakage, neutrophil infiltration, adhesion molecules, cytokine production (e.g., ICAM-1, TNF-α, IL-1β, and IL-2), and the transcription factor nuclear factor of activated T cells c1 nuclear translocation in the lung tissue. These findings indicate that BTP2 can be a potential therapeutic drug for lung I/R injury and suggest that SOCC may play a critical role in lung I/R injury.

The Effects of Insulin-Like Growth Factor I and BTP-2 on Acute Lung Injury

“…LPS causes increased cytosolic calcium in several different cell types, including immune cells, endothelial cells, and epithelial cells [ 29 , 55 ]. Importantly, BTP-2 has been shown to decrease the release of proinflammatory cytokines [ 18 , 24 , 56 ], indicating that the observed consequences to the BTP-2 treatment are calcium-dependent. However, improvements in tissue damage are not limited to the local actions of BTP-2 on a given tissue.…”

“…There are several potential inhibitors of SOCE [ 23 ]. However, we chose BTP-2, because it has been used successfully in experimental animals to suppress the immune system in severe inflammatory conditions, including ALI [ 24 ]. The immunosuppressive activity of BTP-2 is similar to cyclosporine, but cyclosporine is reportedly more toxic.…”

Stromal-Interacting Molecule 1 (Stim1)/Orai1 Modulates Endothelial Permeability in Ventilator-Induced Lung Injury

“…Then, the activation of Stim proteins follows a similar pattern of aggregation and translocation into ER-plasma membrane junctions and combines directly with the highly Ca 2+ -selective family of Orai channels to generate Ca 2+ entry signals [30,31]. BTP2, a store-operated calcium channel inhibitor, inhibits Orai1 channel, blocks Ca 2+ influx, and plays an important role in attenuating ischemia-reperfusion injury, thus regulating immune response and relieving inflammation [32–35]. BTP2 pretreatment significantly inhibited the calcium influx after stretching stimulation through Orai1 channel.…”

Ion Channels in Pulmonary Hypertension: A Therapeutic Interest?

“…In vivo, BTP2 administration attenuates lung ischemia–reperfusion injury in rats [ 253 ]. Moreover, in vivo application of BTP2 also prevents the antigen-induced T cell responses that participate in autoimmune diseases [ 254 ].…”