Advances in Ischemia and Reperfusion

Many are the references that pertain to ischemia reperfusion (IR) in the literature, especially in the last 20 years where there has been a dedicated commitment of scientists, physicians and surgeons to advance the field of IR (1–3). All organs have been studied in the past and the majority of therapeutic developments as it pertain to cardiovascular, neurological, digestive, renal and other surgical diseases frequently seen in clinical practice (4, 5).

Because of the interest of so many dedicated professionals, this issue is oriented to review several recent advances. In particular, those that have made some progress in the treatment or understanding of the IR phenomenon. We have considered any work with the potential to establish a link to other developments in the ischemia and reperfusion field.

One editorial and eight scientific works are assembled in this special IR themed issue. These works are ranging from new methods to treat IR injury, characteristics defining IR, consequences of this lesion, new methodologies and new animal models of disease. We are pleased that our issue is international, including works from the United States, Japan, Turkey, England, Greece and China.

THE EDITORIAL NOTE

In the editorial note, I reflect on the evolution of the ischemia and reperfusion field as interest in this area that started in 1879 (6). It is evident that early attention was concentrated in some isolated case reports and later on possible treatment options since the physio-pathological mechanism was not understood at the time. In the same way, it was not until the discovery of the structure of DNA in 1953 and the molecular sciences years later, that the role of the molecular mediators became actively involved in the field of IR (1–5). The aim of this note is to recognize the outstanding number of publications addressing the understanding and development of IR to define how the field has moved ahead over the last 100 years (7).

PROTECTIVE EFFECT OF NITRIC OXIDE IN LIVER ISCHEMIA AND REPERFUSION

In this original work, Toshihiro and his associates (8) from Nagasaki University Graduate School of Biomedical Sciences, have utilized sodium nitroprusside as an exogenous nitric oxide (NO) donor. The goal was to determine its effect in preserving total hepatic flow while protecting pigs from ischemic injury. Their results demonstrated that sodium nitroprusside administered into the portal vein increased hepatic arterial flow during IR. These studies confirmed the role of an exogenous NO donor in increasing blood flow as a mechanism of protection in liver tissue undergoing IR. The protective effect of exogenous NO donors in rat kidneys subjected to ischemic injury was first reported in 1994 (9). Since then, the field has expanded a great deal and today Toshihiro and associates (8) point out to the protective effect of using this compound in ischemically injured organs such as the liver.

NEBIVOLOL (BETA 1 BLOCKER) DECREASES HEPATIC ISCHEMIA REPERFUSION INJURY

Beta blockers have made significant contributions to cardiovascular medicine. In this work, Ulger and his group (10) from Dicle University in Turkey examined how a beta 1 blocker, Nebivolol, protected rat ischemic livers from severe injury. The use of this beta 1 blocker demonstrated that oxidative stress and pathological ischemic findings were reduced after 30 minutes of liver vascular occlusion. The results using Nebivolol are encouraging for the beta 1 blocking effect or for other similar compounds studied under clinical conditions of liver IR. However, interestingly enough, there was no protection of distant organs such as the kidneys or lungs after liver ischemia and reperfusion.

ISCHEMIC PRECONDITIONING ATTENUATES OXIDATIVE STRESS OF INTRA-ABDOMINAL HYPERTENSION

Since the preliminary works of Murry et al ischemic preconditioning (IPC) has become a more established entity (11). Leventi and his colleagues (12) from London Whittington Hospital and the Aretaieion University Hospital and the University of Athens in Greece studied whether the phenomenon of IPC attenuated oxidative stress after intra-abdominal hypertension (IAH). It was evident that IPC diminished oxidative stress in pigs with IAH. It also had a protective effect through the nitrite mechanism of protection but did not have an effect on nitrates or total NO. The work of these investigators better defined how a physiological event of preconditioning could be beneficial in cases of IAH. More studies are needed to complete our understanding of this potential therapeutic measure.

ISCHEMIC PRECONDITIONING, IRON CHELATION AND HEPATECTOMY

Next, Trogadas and his associates (13) from the University of Athens and the Attikon University Hospital in Greece demonstrated in pigs that lower intracranial pressure (ICP) levels correlated well with ischemic preconditioning and desferoxamine modalities of treatment. This study also advanced the notion that ischemic preconditioning protects the liver probably by upregulating protective mechanisms of inflammatory mediators. Furthermore, desferoxamine, an iron chelating agent, could block the production of free radicals and other mediators of inflammation. Also, the histological response after IR and partial extensive hepatectomy was attenuated following ischemic preconditioning and desferoxamine.

TEMPOL (HYDROXYL RADICAL SCAVENGER) REDUCED ACUTE NECROTIZING PANCREATIC INJURY

We considered acute necrotizing pancreatitis (ANP) part of the family of the ischemic disorders. Erbis and his associates (14) from the Faculties of Medicine of Akdeniz, Pamukkale and Adnan Menderes Universities in Turkey studied the role of tempol on experimental ANP in rats. Their work emphasized how the control of hydroxyl radicals favored the treatment of acute pancreatic injury following the necrotizing model. Beneficial effects of this drug have been observed in ischemia reperfusion of the myocardium, kidneys, brain and intestine (14). The possibility of using this drug in cases of ischemic injury is encouraging and may potentially be used alone or in combined with other compounds that may improve IR recovery.

NEW SEGMENTAL HEPATECTOMY WITH A REVERSIBLE THERMOSENSITIVE GEL INTO THE PORTAL VEIN

This new methodology paper from Wang and his group (15) from the Institute of Hepatobiliary Surgery of the Chinese PLA Medical College in Beijing, China present a potentially better model for clinical liver surgery resection with decreased ischemic injury. They have developed the use of a new safe and simple method of segmental hepatectomy in pigs. Using a reversible thermosensitive gel (Poloxamer 407, P407) that “can instantly transform into a stiff gel that occludes blood flow and dissolves spontaneously within 30 minutes of being injected into a vessel” (15). This method provides a significant advantage when compared to the old methylene blue stain technique (15). The liver segmentectomy approach using this method could effectively improve the way we protect livers for general, cancer or transplant surgery procedures.

A SURGICAL TECHNIQUE TO STUDY LIVER ISCHEMIA REPERFUSION IN THE MICE

Advances in surgical techniques are not simple to incorporate and maintain when operating in small animals like the mice. This issue introduces a surgical model of liver ischemia reperfusion injury developed by Jianjian Zhang and his associates (16) from Renji Hospital School of Medicine at the Shanghai Jiaotong University in Shanghai, China. In their technique of liver ischemia they cross-clamped the blood supply to the left lateral lobe (35% of the liver mass) of the mice. One drawback of this 35% liver ischemia technique, is the fact that no survival studies were performed and therefore it would be difficult to compare it to other techniques published in the literature (17). Nevertheless, the authors have extensively proven the applicability of this surgical technique in a large number of animals performed in their experiments. This useful technique will present opportunities for testing and comparing IR in the mouse liver.

SELECTINS IN LIVER ISCHEMIA AND REPERFUSION

The review paper by Jones et al (18) concentrated in defining the role of selectin molecules in liver ischemia reperfusion. Selectins were determined to be an important part of the IR injury and their downregulation is critical to the protection of ischemichally damaged livers. Specific studies on each of the three selectins defined how each one of them participate in protecting organs from ischemic injury. Overall, further study is needed on selectins to ascertain their function and capability in IR conditions.

CONCLUSION

This thematic issue added new information to the field of ischemia and reperfusion injury. The articles utilized herein represent recent advances obtained within this particular area of concentration. It is our hope that the utilization of the principles gathered with these papers would permit further clinical progress in the protection of ischemically damaged organs.