Zhao Lab Research


Our lab mainly studies the protective effect of ischemic postconditioning and remote conditioning against stroke. Reperfusion (the restoration of blood flow) is one of the first choices for ischemic stroke treatment. However, reperfusion can also cause an overproduction of reactive oxygen species (ROS) or free radicals that lead to reperfusion injury. Limiting the damage caused by reperfusion is a key issue for stroke treatment. We were the first to demonstrate that interrupting the early hyperemic response after reperfusion reduces infarction after stroke, a novel phenomenon called postconditioning. Since postconditioning is performed after reperfusion, it has great potential for clinical application. In addition, we also study the protective effect of remote pre- or postconditioning, in which a brief ischemia is induced in a remote,non-vital organ.  Furthermore, injury induced by stroke is not only restricted in the brain, but is also involved in multiple peripheral organ damage, in particular, immunodepression, which is one major cause of mortality in stroke patients. We have been studying the interactive effects between ischemic brain injury and circulating leukocyte functions.  Our aim is to, not only providing insights for treating brain injury, but also for attenuating immunodepression.

Ischemic Postconditioning

In 2006, our laboratory made the novel discovery that ischemic postconditioning reduces infarct size after focal ischemia. We showed that ischemic postconditioning performed immediately after reperfusion significantly reduced infarct size in a focal ischemia model in rats. In the past several years, we have studied the protective effects of both rapid postconditioning, which is performed immediately after reperfusion, and delayed postconditioning, which is performed a few hours after reperfusion. A number of independent laboratories in the USA and abroad have confirmed our findings. Our articles have been extensively cited by these subsequent studies. Our innovative seed studies have opened an important new research direction in the stroke field with tangible benefits. After establishing the protective effects of rapid and delayed ischemic postconditioning, we next studied the protective parameters of ischemic postconditioning and found that the protective effects depend on its onset, the number of cycles of stuttering reperfusion, and the duration of each cycle. In addition, we also studied the underlying protective mechanisms of ischemic postconditioning, including the roles of the Akt, Erk/JNK, and PKC pathways. Recently, we have further established an ischemic postconditioning model in mice, which enable us to study the underlying protective mechanism of ischemic postconditioning by utilizing various transgenic animals.

Remote Limb Preconditioning or Postconditioning

I have further extended the conventional concepts of ischemic pre- and postconditioning to remote pre- and postconditioning. Remote pre- or postconditioning refers to ischemia performed in a non-vital organ that protects against ischemic injury to a vital organ. Classical or traditional ischemic pre- or postconditioning is performed on the ischemic brain; therefore, the performance itself may endanger the brain. However, because remote pre- or postconditioning is conducted in a non-vital organ, it has the potential to be far safer when translated for clinical applications. We are among the first to show that both remote ischemic pre- and postconditioning performed in the hind limb with the repetitive occlusion and release of the femoral artery can reduce brain infarction induced by focal brain ischemia in rats. Several research hospitals in the USA, China and Europe are now performing clinical trials on remote preconditioning for stroke patients, and some have reported positive results. We believe our pioneering studies are critical to these advances toward clinical application.

Interactive effects between the immune system and brain injury induced by stroke

Bidirectional effects occur between the injured brain and the peripheral immune system after stroke. On one hand, the peripheral immune system increases local brain inflammation via recruitment and infiltration of circulating neutrophils, macrophages and T cells, thus exacerbating ischemic injury. Recently, we successfully identified distinctive roles of T cell subsets demonstrating that the paucity of CD4 or CD8 T cells equally resulted in brain injury after stroke. In addition, we found that, although a functional deficiency of regulatory T cells had no effect, impaired Th1 immunity reduced infarction and impaired Th2 immunity aggravated brain injury. Our research suggests that the peripheral immune system is a potential target for stroke treatment.  On the other hand, brain injury induced by stroke causes significant immune depression, which results in severe pneumonia leading to death in stroke patients. Our laboratory has been interested in studying whether mild to moderate hypothermia, as well as glycyrrhizin, a natural anti-inflammatory product, has significant effects on immune depression induced by stroke. We aim to explore pharmacological and non-pharmacological agents to attenuate immune depression. Based on the two aspects as described above, our current studies focus on the detrimental mechanisms of peripheral lymphocytes monocytes/macrophages on brain injury, and how these peripheral leukocytes pass detrimental signals to brain resident inflammatory macrophages. We are also studying how the nature and behavior of peripheral leukocytes are affected by brain injury.