Understanding the Origins of Ischemia and Reperfusion

Ischemia and reperfusion injury (IR) is a complex pathological condition directly associated with lack of blood supply and therefore poor oxygenation followed by reintroduction of blood/oxygen during reperfusion. This condition creates a series of metabolic and molecular events that dramatically change the response of the cell to injury. Some believe that IR in humans has as many pathological events as those present in the most complicated clinical conditions. In this editorial note, we briefly review how the term or pathology associated with IR has evolved through the ages as far as we can define in an extensive literature review assessment.

The terms ischemia and reperfusion, alone or combined, is relatively old describing a phenomenon frequently seen as a result of thrombosis or embolus formation. When one searches the term “ischemia” in PubMed, 232, 895 citations were encountered (1). The first clinical report of ischemia occurred more than 100 years ago, in 1879, describing “Ischaemia of the Retinal Vessels of both eyes following Facial Erysipelas” (2).

After the 1879 publication, another report followed “Certain Cases of Functional Ischemia of the Brain” published in 1880 (3). According to PubMed, these reports appeared to be the first medical publications dealing with ischemic events. Years later, in 1934, Goldblatt and his team, published works in experimental hypertension and the production of persistent high blood pressure after renal ischemia (4). This study was a landmark description of renal ischemia and its implications on the development of hypertension. Currently, 16,582 publications have been encountered when “renal ischemia” was used as the principal denominator for PubMed related publications (5).

In 1937, Lavine and Upcott published the first article dealing with myocardial ischemia treated by a graft of skeletal muscle to the heart (6). Presently there are 66,125 articles in PubMed relating to the term “heart ischemia” (7). In other abdominal organs besides the kidney, liver ischemia has been frequently cited with 11,154 publications when the term “liver ischemia” was searched (8). The first paper that mentioned liver ischemia, published in 1947, was written by P. Drochmans and described “The Effect of Ischaemia on Nucleoproteins in Liver Cells” (9).

The numbers previously introduced are a testimony of the interest the medical and scientific community have in IR. This interest is related to the frequency with which the pathology associated with ischemia is often seen in the industrialized world. In 1951, Kunlin et al published the first paper concerning “ischemia and transplantation”. There are currently 18,788 citations (10) since their first report discussing “Long Vein Transplantation in treating of Ischemia Caused by Arteritis” (11).

After all this information, where does IR start? And how can we better understand the origins of this pathology? Is there a specific seminal event that created a well-defined change in human pathology? Or are we just speaking of a phenomenon that has always existed for all times but has been better described more recently? What is the right response for these questions that we believe are significant but sometimes without well-integrated answers? What are the steps needed to reconcile the IR elements of appearance and meaning for human pathology? Let us try to solve some of these intriguing and elemental concerns we have related to IR development.

IR starts immediately after vessel occlusion whatever that might be. Subsequently, reperfusion further empowers molecular and tissue elements to increase to the highest level the ischemic lesion. Up to the 1960s, there were few scientists that understood the reach of IR. However, attempted works at defining the IR lesion go as far back as the late 19^th century. Today, we know that reperfusion is the determinant element of the ischemic lesion. Reperfusion is needed for ischemia to cause its lesion-effect-injury and final pathology. The beginning of the lesion is now believed to originate at the time of re-infusion of blood to the ischemic organ.

The seminal event from which all of the IR injury begins is at the inflammation level generated through neutrophils and other immune cells which quickly respond to the combined damage caused by the dual injury seen after IR. It took many years to characterize this lesion that appears simple but has been problematic to recognize what causes damage after its inception. Subsequent to the initial immune damage other elements get activated like platelets, complement, regulatory T-cells, dendritic cells, and other elements of the inflammatory machinery (12, 13). Previous work by our group has presented various solutions to the definition and improvement of this lesion (12–15).

As suggested before, IR has always existed but better methods of study have advanced our knowledge of the lesion and define the origins more accurately. IR starts with ischemia and is enhanced by reperfusion when all the immune response begins to repair the ischemia, creating the lesion. The final question of how to overcome the pathology with better therapeutics is not simple yet we are in the process of determining the best way to treat this lesion but we do not have a final answer due to the fact that IR changes its response depending on the severity of the lesion, relative to time and intensity.

As we conclude this editorial note, many things are clear but others remain undefined. We need to advance how we assess IR injury, and better define the mechanisms of injury and protection. We need to have better methods to treat the IR lesion. We need to better understand the precise mechanisms of injury. We need to better define which factors increase morbidity and mortality when treating patients with IR. In sum, better knowledge of the lesion, leads to better means to treat it.