Surgical Inflammation

The concept of inflammation throughout its history has become exceedingly enhanced by the discovery that inflammation does not just participate in conditions that produce redness, swelling, heat, pain and loss of function. Nowadays, inflammation is associated with numerous and diverse diseases, including arterial hypertension, atherosclerosis, type 2 diabetes, neurodegeneration and cancer. In addition, inflammation is a process also involved in many physiological processes like embryogenesis, regeneration, aging and animal development. Understanding the great versatility of the inflammatory response is very useful for surgeons given its application potential during pre-, intra- and postoperative management of their patients.

Tetrapyrrole molecules are distributed in virtually all living organisms on Earth. In mammals, tetrapyrrole end products are closely linked to oxygen metabolism. Since increasingly complex trophic functional systems for using oxygen are considered in the post-traumatic inflammatory response, it can be suggested that tetrapyrrole molecules and, particularly their derived pigments, play a key role in modulating inflammation. In this way, the diverse colorfulness that the inflammatory response triggers during its evolution would reflect the major pathophysiological importance of these pigments in each one of its phases. Hence, the need of exploiting this color resource could be considered for both the diagnosis and treatment of the inflammation.

Post-traumatic inflammation is formed by molecular and cellular complex mechanisms whose final goal seems to be injured tissue regeneration. In the skin, an exterior organ of the body, mechanical or thermal injury induces the expression of different inflammatory phenotypes that resemble similar phenotypes expressed during embryo development. Particularly, molecular and cellular mechanisms are involved in gastrulation return. This is a developmental phase that delineates the three embryonic germ layers: ectoderm, endoderm and mesoderm. Consequently, in the post-natal wounded skin primitive functions related with the embryonic mesoderm, i.e. amniotic and yolk sac-derived, are expressed. Among the primitive function mechanisms involved, neurogenesis and hematogenesis stand out as the prominent ones.

Interestingly, in these phases of the inflammatory response, whose molecular and cellular mechanisms are considered as traces of the early phases of the embryonic development, the mast cell, a cell that is supposedly inflammatory, plays a key role. The correlation that can be established between the embryonic and the inflammatory events suggests that the results obtained from the research regarding both great fields of knowledge must be interchangeable to obtain the maximum advantage.

The surgical inflammatory response can be a type of high-grade acute stress response associated with an increasingly complex trophic functional system for using oxygen. This systemic neuro-immune-endocrine response seems to induce the reexpression of 2 extraembryonic-like functional axes, i.e. coelomic-amniotic and trophoblastic-yolk-sac-related, within the injured tissues and organs, thus favoring their re-development. Accordingly, through the up-regulation of two systemic inflammatory phenotypes, i.e. neurogenic and immune-related, a gestational-like response using embryonic functions would be induced in the patient's injured tissues and organs, which would therefore result in their repair. A comparison has been established between the pahtophysiological mechanisms that are produced during the inflammatory response and the physiological mechanisms that are expressed during early embryonic development. Surgical inflammation could be a high-grade stress response whose pathophysiological mechanisms would be based on the recapitulation of ontogenic and phylogenetic-related functions. Thus, the ultimate objective of surgical inflammation, as a gestational process, is creating new tissues/organs for repairing the injured ones. Since surgical inflammation and early embryonic development share common mechanisms of production, the factors that hamper the wound healing reaction in surgical patients could be similar to those that impair the gestational process.

The cutaneous wound healing reaction occurs in overlapping but inter-related phases which finally involves fibrosis. The pathophysiological mechanisms involved in fibrotic diseases, including those organ-related or even systemic, like systemic sclerosis, could represent the successive systemic upregulation of extraembryonic-like phenotypes, i.e.: amniotic and vitelline. These two extraembryonic-like phenotypes would focus on the injured tissue to induce a process similar to that occurs in the early phases of embryo development, which is gastrulation. The amniotic-like phenotype would play a leading role in the development of a neurogenic response with noteworthy hydroelectrolytic alterations that essentially would represent the creation of an open microcirculation in the injured tissue. In turn, through the overlapped expression of a vitelline-like phenotype, a bone-marrow-related response is produced. The interstitial infiltration by molecular and cellular mediators contributed by the amniotic- and vitelline-like functions provides the functional and metabolic autonomy which is needed for inducing the formation of a new tissue by using mechanisms similar to those expressed in gastrulation during the early phases of the embryo development. Thus, a new tissue is formed but unfortunately it quickly evolves by premature senescence to fibrosis. The hypothesized use of mechanisms is related to extraembryonic-like functions in the three following physiological and pathological processes: the embryonic development; the wound healing reaction during adult life and, finally in senescence, where the existence of a basic self-organizing fractal-like functional pattern as an essential characteristic of our way of life is suggested.

An interpretation of the metabolic response to injury in patients with severe accidental or surgical trauma is made. In the last century, various authors attributed a meaning to the post-traumatic inflammatory response by using theleological arguments. Their interpretations of this response, not only facilitate integrating the knowledge, but also their flow from the bench to the bedside, which is the main objective of modern translational research. The goal of the current review is to correlate the metabolic changes with the three phenotypes -ischemia-reperfusion, leukocytic and angiogenic that the patients express through the evolution of the systemic inflammatory response. The sequence in the expression of multiple metabolic systems that becomes progressively more elaborate and complex in severe injured patients urges for more detailed knowledge in order to establish the most adequate metabolic support according to the evolutive phase.

The inflammatory response related to surgery is a systemic reaction considered as the expression of three overlapping trophic phases during which the oxygen consumption progressively increases. However, surgical inflammation could induce old functions in which life on the Earth has based on the expression of two hypothetical extraembryonic trophic axes i.e. coelomic-amniotic and trophoblastic-yolk sac related, when integrated in the interstitium of the injured tissues and organs to induce a gastrulation-related phenotype. This later phenotype would repair the tissues by fibrosis and/or regeneration. A coupling of this recapitulated extraembryonic axis would cause hyperacute or acute–on-chronic inflammation or sepsis. The mechanisms of this systemic inflammatory response could be reminiscences of some phylogenetic mechanisms that ultimately would favor a metabolic cross-talk between the eukaryotic cell and gut microbiome. These ontogenic and phylogenic hypotheses of the surgical inflammatory and septic responses could open new research pathways about the ancient co-evolution of humans with their microbiota.

Inflammation has been implicated in tumor development, invasion and metastasis. Hence, it has been suggested that common cellular and molecular mechanisms are activated in wound repair and in cancer development. In addition, it has been previously proposed that the inflammatory response, which is associated with the wound healing process, could recapitulate ontogeny through the re-expression of the extraembryonic, i.e. amniotic and vitelline, functions in the interstitial space of the injured tissue. If so, the use of inflammation by the cancer-initiating cell can also be supported in the ability to reacquire extraembryonic functional axes for tumor development, invasion and metastasis. Thus, the diverse components of the tumor microenvironment could represent the overlapped re-expression of amniotic and vitelline functions. These functions would favor a gastrulation-like process, that is, the creation of a reactive stroma in which fibrogenesis and angiogenesis appear.

Mesenchymal stem cells (MSCs) are used in regenerative medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors. Moreover, MSCs can stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation and antibody secretion; DC maturation and activation; as well as antigen presentation. In this scenario, an inflammatory environment seems to be necessary to promote their effect. Preclinical studies have been conducted in rodents, rabbits and baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft-vs.-host disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, and diabetes and lupus diseases. Preliminary results from some of these studies have led to human clinical trials; prevention of allograft rejection and enhancement of the survival of bone marrow and kidney grafts.

Inflammation integrates diverse mechanisms that are associated not only with pathological conditions, such as cardiovascular diseases, type 2 diabetes, obesity, neurodegenerative diseases and cancer, but also with physiological processes like reproduction i.e., oogenesis and embryogenesis as well as aging. In the current review, we propose that the inflammatory response could also recapitulate the phylogenia and the ontogenia. Highly conserved inflammatory mechanisms that play a main role in the evolutive development of different animal species, both invertebrates as well as vertebrates are identified. In this way, inflammation could represent a key tool used by nature to modulate organisms according to the environmental conditions in which these develop. Thus inflammation could be the pathway by which the environmental conditions could be related to the evolutionary development. The hypothetical consideration of inflammation as recapitulation of phylogenia and ontogenia could make it possible to integrate the pathophysiological mechanisms of these diverse chronic pathological conditions.

Prehepatic portal hypertension induces a splanchnic low-grade inflammatory response that could switch to high-grade inflammation with the development of severe and life-threatening complications when associated with chronic liver disease. The extraembryonic origin of the portal system may determine the regression to an extraembryonic phenotype i.e., vitellogenic and amniotic, during the evolution of both types of portal hypertension. Thus prehepatic portal hypertension, or compensated hypertension by portal vein ligation in the rat, is associated with molecular mechanisms related to vitellogenesis, where hepatic steatosis and splanchnic angiogenesis stand out. In turn, extrahepatic cholestasis in the rat induces intrahepatic portal hypertension, or decompensated hypertension, with ascites and hepatorenal syndrome. The splanchnic interstitium, the mesenteric lymphatic system, and the peritoneal mesothelium seem to create an inflammatory pathway that could have a key pathophysiological relevance in the production of ascites. The hypothetical comparison between the ascitic and the amniotic fluid also allows for translational investigation. The induced regression of the splanchnic system to extraembryonic functions by portal hypertension highlights the great relevance of the extraembryonic structures even during post-natal life.