Origin and Consequences of Necroinflammation.

When cells undergo necrotic cell death in either physiological or pathophysiological settings in vivo, they release highly immunogenic intracellular molecules and organelles into the interstitium and thereby represent the strongest known trigger of the immune system. With our increasing understanding of necrosis as a regulated and genetically determined process (RN, regulated necrosis), necrosis and necroinflammation can be pharmacologically prevented. This review discusses our current knowledge about signaling pathways of necrotic cell death as the origin of necroinflammation. Multiple pathways of RN such as necroptosis, ferroptosis, and pyroptosis have been evolutionary conserved most likely because of their differences in immunogenicity. As the consequence of necrosis, however, all necrotic cells release damage associated molecular patterns (DAMPs) that have been extensively investigated over the last two decades. Analysis of necroinflammation allows characterizing specific signatures for each particular pathway of cell death. While all RN-pathways share the release of DAMPs in general, most of them actively regulate the immune system by the additional expression and/or maturation of either pro- or anti-inflammatory cytokines/chemokines. In addition, DAMPs have been demonstrated to modulate the process of regeneration. For the purpose of better understanding of necroinflammation, we introduce a novel classification of DAMPs in this review to help detect the relative contribution of each RN-pathway to certain physiological and pathophysiological conditions.

Role of DAMPs and cell death in autoimmune diseases: the example of multiple sclerosis.

Multiple sclerosis is a chronic neuroinflammatory demyelinating disease of the central nervous system (CNS) of unknown etiology and still incompletely clarified pathogenesis. The disease is generally considered a disorder resulting from a complex interplay between environmental risk factors and predisposing causal genetic variants. To examine the etiopathogenesis of the disease, two complementary pre-clinical models are currently discussed: the "outside-in" model proposing a peripherally elicited inflammatory/autoimmune attack against degraded myelin as the cause of the disease, and the "inside-out" paradigm implying a primary cytodegenerative process of cells in the CNS that triggers secondary reactive inflammatory/autoimmune responses against myelin debris. In this review, the integrating pathogenetic role of damage-associated molecular patterns (DAMPs) in these two scenario models is examined by focusing on the origin and sources of these molecules, which are known to promote neuroinflammation and, via activation of pattern recognition receptor-bearing antigen-presenting cells, drive and shape autoimmune responses. In particular, environmental factors are discussed that are conceptually defined as agents which produce endogenous DAMPs via induction of regulated cell death (RCD) or act themselves as exogenous DAMPs. Indeed, in the field of autoimmune diseases, including multiple sclerosis, recent research has focused on environmental triggers that cause secondary events in terms of subroutines of RCD, which have been identified as prolific sources of DAMPs. Finally, a model of a DAMP-driven positive feed-forward loop of chronic inflammatory demyelinating processes is proposed, aimed at reconciling the competing "inside-out" and "outside-in" paradigms.

Role of DAMPs in respiratory virus-induced acute respiratory distress syndrome-with a preliminary reference to SARS-CoV-2 pneumonia.

When surveying the current literature on COVID-19, the "cytokine storm" is considered to be pathogenetically involved in its severe outcomes such as acute respiratory distress syndrome, systemic inflammatory response syndrome, and eventually multiple organ failure. In this review, the similar role of DAMPs is addressed, that is, of those molecules, which operate upstream of the inflammatory pathway by activating those cells, which ultimately release the cytokines. Given the still limited reports on their role in COVID-19, the emerging topic is extended to respiratory viral infections with focus on influenza. At first, a brief introduction is given on the function of various classes of activating DAMPs and counterbalancing suppressing DAMPs (SAMPs) in initiating controlled inflammation-promoting and inflammation-resolving defense responses upon infectious and sterile insults. It is stressed that the excessive emission of DAMPs upon severe injury uncovers their fateful property in triggering dysregulated life-threatening hyperinflammatory responses. Such a scenario may happen when the viral load is too high, for example, in the respiratory tract, "forcing" many virus-infected host cells to decide to commit "suicidal" regulated cell death (e.g., necroptosis, pyroptosis) associated with release of large amounts of DAMPs: an important topic of this review. Ironically, although the aim of this "suicidal" cell death is to save and restore organismal homeostasis, the intrinsic release of excessive amounts of DAMPs leads to those dysregulated hyperinflammatory responses-as typically involved in the pathogenesis of acute respiratory distress syndrome and systemic inflammatory response syndrome in respiratory viral infections. Consequently, as briefly outlined in this review, these molecules can be considered valuable diagnostic and prognostic biomarkers to monitor and evaluate the course of the viral disorder, in particular, to grasp the eventual transition precociously from a controlled defense response as observed in mild/moderate cases to a dysregulated life-threatening hyperinflammatory response as seen, for example, in severe/fatal COVID-19. Moreover, the pathogenetic involvement of these molecules qualifies them as relevant future therapeutic targets to prevent severe/ fatal outcomes. Finally, a theory is presented proposing that the superimposition of coronavirus-induced DAMPs with non-virus-induced DAMPs from other origins such as air pollution or high age may contribute to severe and fatal courses of coronavirus pneumonia.

Transfusion-Related Acute Lung Injury: The Work of DAMPs.

Current notions in immunology hold that not only pathogen-mediated tissue injury but any injury activates the innate immune system. In principle, this evolutionarily highly conserved, rapid first-line defense system responds to pathogen-induced injury with the creation of infectious inflammation, and non-pathogen-induced tissue injury with 'sterile' tissue inflammation. In this review, evidence has been collected in support of the notion that the transfusion-related acute lung injury induces a 'sterile' inflammation in the lung of transfused patients in terms of an acute innate inflammatory disease. The inflammatory response is mediated by the patient's innate immune cells including lung-passing neutrophils and pulmonary endothelial cells, which are equipped with pattern recognition receptors. These receptors are able to sense injury-induced, damage-associated molecular patterns (DAMPs) generated during collection, processing, and storage of blood/blood components. The recognition process leads to activation of these innate cells. A critical role for a protein complex known as the NLRP3 inflammasome has been suggested to be at the center of such a scenario. This complex undergoes an initial 'priming' step mediated by 1 class of DAMPs and then an 'activating' step mediated by another class of DAMPs to activate interleukin-1beta and interleukin-18. These 2 cytokines then promote, via transactivation, the formation of lung inflammation.

Incentives for organ donation: proposed standards for an internationally acceptable system.

Incentives for organ donation, currently prohibited in most countries, may increase donation and save lives. Discussion of incentives has focused on two areas: (1) whether or not there are ethical principles that justify the current prohibition and (2) whether incentives would do more good than harm. We herein address the second concern and propose for discussion standards and guidelines for an acceptable system of incentives for donation. We believe that if systems based on these guidelines were developed, harms would be no greater than those to today's conventional donors. Ultimately, until there are trials of incentives, the question of benefits and harms cannot be satisfactorily answered.

Antithrombin therapy in pancreas retransplantation and pancreas-after-kidney/pancreas-transplantation-alone patients.

Antithrombin (AT) is a coagulatory inhibitor with pleiotropic activities. AT reduces ischemia/reperfusion injury and has been successfully used in patients with simultaneous pancreas kidney transplantation. This study retrospectively analyzes prophylactic high-dose AT application in patients with solitary pancreas transplantation traditionally related to suboptimal results. In our center, 31 patients received solitary pancreas transplantation between 7/1994 and 7/2005 (pancreas retransplantation, PAK/PTA). The perioperative treatment protocol was modified in 5/2002 now including application of 3000 IU. AT was given intravenously before pancreatic reperfusion (AT, n = 18). Patients receiving standard therapy served as controls (n = 13). Daily blood sampling was performed during five postoperative days. Standard coagulatory parameters and number of transfused red blood cell units were not altered by AT. In AT patients serum amylase (p < 0.01) and lipase (p < 0.01) on postoperative days 1, 2 and 3 were significantly reduced. Our actual perioperative management protocol including high dose AT application in human solitary pancreas transplantation reduced postoperative liberation of pancreatic enzymes in this pilot study. Prophylactic AT application should deserve further clinical testing in a randomized controlled trial.

Use of DAMPs and SAMPs as Therapeutic Targets or Therapeutics: A Note of Caution.

This opinion article discusses the increasing attention paid to the role of activating damage-associated molecular patterns (DAMPs) in initiation of inflammatory diseases and suppressing/inhibiting DAMPs (SAMPs) in resolution of inflammatory diseases and, consequently, to the future roles of these novel biomarkers as therapeutic targets and therapeutics. Since controlled production of DAMPs and SAMPs is needed to achieve full homeostatic restoration and repair from tissue injury, only their pathological, not their homeostatic, concentrations should be therapeutically tackled. Therefore, distinct caveats are proposed regarding choosing DAMPs and SAMPs for therapeutic purposes. For example, we discuss the need to a priori identify and define a context-dependent "homeostatic DAMP:SAMP ratio" in each case and a "homeostatic window" of DAMP and SAMP concentrations to guarantee a safe treatment modality to patients. Finally, a few clinical examples of how DAMPs and SAMPs might be used as therapeutic targets or therapeutics in the future are discussed, including inhibition of DAMPs in hyperinflammatory processes (e.g., systemic inflammatory response syndrome, as currently observed in Covid-19), administration of SAMPs in chronic inflammatory diseases, inhibition of SAMPs in hyperresolving processes (e.g., compensatory anti-inflammatory response syndrome), and administration/induction of DAMPs in vaccination procedures and anti-cancer therapy.

Role of Damage-Associated Molecular Patterns in Light of Modern Environmental Research: A Tautological Approach.

Two prominent models emerged as a result of intense interdisciplinary discussions on the environmental health paradigm, called the "exposome" concept and the "adverse outcome pathway" (AOP) concept that links a molecular initiating event to the adverse outcome via key events. Here, evidence is discussed, suggesting that environmental stress/injury-induced damage-associated molecular patterns (DAMPs) may operate as an essential integrating element of both environmental health research paradigms. DAMP-promoted controlled/uncontrolled innate/adaptive immune responses reflect the key events of the AOP concept. The whole process starting from exposure to a distinct environmental stress/injury-associated with the presence/emission of DAMPs-up to the manifestation of a disease may be regarded as an exposome. Clinical examples of such a scenario are briefly sketched, in particular, a model in relation to the emerging COVID-19 pandemic, where the interaction of noninfectious environmental factors (e.g., particulate matter) and infectious factors (SARS CoV-2) may promote SARS case fatality via superimposition of both exogenous and endogenous DAMPs.

Damage-associated molecular patterns in trauma.

In 1994, the "danger model" argued that adaptive immune responses are driven rather by molecules released upon tissue damage than by the recognition of "strange" molecules. Thus, an alternative to the "self versus non-self recognition model" has been provided. The model, which suggests that the immune system discriminates dangerous from safe molecules, has established the basis for the future designation of damage-associated molecular patterns (DAMPs), a term that was coined by Walter G. Land, Seong, and Matzinger. The pathological importance of DAMPs is barely somewhere else evident as in the posttraumatic or post-surgical inflammation and regeneration. Since DAMPs have been identified to trigger specific immune responses and inflammation, which is not necessarily detrimental but also regenerative, it still remains difficult to describe their "friend or foe" role in the posttraumatic immunogenicity and healing process. DAMPs can be used as biomarkers to indicate and/or to monitor a disease or injury severity, but they also may serve as clinically applicable parameters for optimized indication of the timing for, i.e., secondary surgeries. While experimental studies allow the detection of these biomarkers on different levels including cellular, tissue, and circulatory milieu, this is not always easily transferable to the human situation. Thus, in this review, we focus on the recent literature dealing with the pathophysiological importance of DAMPs after traumatic injury. Since dysregulated inflammation in traumatized patients always implies disturbed resolution of inflammation, so-called model of suppressing/inhibiting inducible DAMPs (SAMPs) will be very briefly introduced. Thus, an update on this topic in the field of trauma will be provided.

Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients.

BACKGROUND: Acute respiratory distress syndrome continues to drive significant morbidity and mortality after severe trauma. The incidence of trauma-induced, moderate-to-severe hypoxaemia, according to the Berlin definition, could be as high as 45%. Its pathophysiology includes the release of damage-associated molecular patterns (DAMPs), which propagate tissue injuries by triggering neutrophil extracellular traps (NETs). NETs include a DNA backbone coated with cytoplasmic proteins, which drive pulmonary cytotoxic effects. The structure of NETs and many DAMPs includes double-stranded DNA, which prevents their neutralization by plasma. Dornase alfa is a US Food and Drug Administration-approved recombinant DNase, which cleaves extracellular DNA and may therefore break up the backbone of NETs and DAMPs. Aerosolized dornase alfa was shown to reduce trauma-induced lung injury in experimental models and to improve arterial oxygenation in ventilated patients. METHODS: TRAUMADORNASE will be an institution-led, multicentre, double-blinded, placebo-controlled randomized trial in ventilated trauma patients. The primary trial objective is to demonstrate a reduction in the incidence of moderate-to-severe hypoxaemia in severe trauma patients during the first 7 days from 45% to 30% by providing aerosolized dornase alfa as compared to placebo. The secondary objectives are to demonstrate an improvement in lung function and a reduction in morbidity and mortality. Randomization of 250 patients per treatment arm will be carried out through a secure, web-based system. Statistical analyses will include a descriptive step and an inferential step using fully Bayesian techniques. The study was approved by both the Agence Nationale de la Sécurité du Médicament et des Produits de Santé (ANSM, on 5 October 2018) and a National Institutional Review Board (CPP, on 6 November 2018). Participant recruitment began in March 2019. Results will be published in international peer-reviewed medical journals. DISCUSSION: If early administration of inhaled dornase alfa actually reduces the incidence of moderate-to-severe hypoxaemia in patients with severe trauma, this new therapeutic strategy may be easily implemented in many clinical trauma care settings. This treatment may facilitate ventilator weaning, reduce the burden of trauma-induced lung inflammation and facilitate recovery and rehabilitation in severe trauma patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03368092. Registered on 11 December 2017.

[50 Years ago: First Successful Treatment of Acute Allograft Rejection after a Human Heart Transplantation]. / Vor 50 Jahren: Erste erfolgreiche Behandlung einer akuten Herztransplantat-Abstoßungskrise.

The first clinical use of the "Munich antilymphocyte globulin" (ALG) at the occasion of the first successful human heart transplantation is briefly described. The cardiac transplantation was carried out by Christiaan Barnard and his team in Cape Town, South Africa, in 1968. The patient developed an acute allograft rejection which could be successfully reversed within three weeks using the intravenous administration of ALG. This event can be regarded as the beginning of a success story of ALG in its use as a powerful immunosuppressive agent in all categories of clinical organ transplantation.

Innate alloimmunity: history and current knowledge.

The history of innate alloimmunity begins in 1994 with the publication of clinical data from the Munich superoxide dismutase trial, which suggests that renal allograft reperfusion injury initiates acute allograft rejection and contributes to the development of chronic rejection. This clinical observation led to construction of an Injury Hypothesis. By 2007, growing evidence in favor of this hypothesis was seen. In particular, there was increasing experimental evidence in support of the notion that an oxidative allograft injury leads to generation of damage-associated molecules, such as heat shock protein 72, high mobility group box 1, and a hyaluronan fragment, all of which act as endogenous ligands of Toll-like receptors. These molecules are recognized by intragraft donor-derived and recipient-derived, Toll-like receptor 4- and Toll-like receptor 2-bearing dendritic cells that mature and subsequently initiate cytokine-driven development of the recipient's adaptive alloimmune response. Initial evidence suggests that injury-induced, Toll-like receptor-triggered signaling pathways involved in establishing innate alloimmunity utilize adaptor proteins and transcription factors that play a crucial role in the host's defense against pathogens.

Immunosuppressive strategies in organ transplantation in the light of innate immunity.

Evidence has accumulated to support the notion that injury-induced activation of the donor's and the recipient's innate immune system largely determines the outcome of organ transplantation. Future potential therapeutic strategies to suppress events of both innate immune systems, as well as approaches to mitigate allograft injury, are discussed with regard to inhibiting both complement activation and dendritic cell maturation, and to blocking innate effector functions. Applications of pharmacological drug therapy as well as gene-specific manipulations are theoretical tools to reach these goals. A variety of encouraging experimental data in this research field are already available and promise further discoveries that ultimately will lead to the design of appropriate clinical trials.

Toxicity-sparing protocols using mycophenolate mofetil in renal transplantation.

The introduction of triple-therapy regimens that include a calcineurin inhibitor (CNI), steroids, and azathioprine greatly reduced the risk of acute rejection in renal transplantation. However, the long-term use of both CNIs and steroids is associated with serious toxicities that ultimately can impact patient/graft survival. Mycophenolate mofetil (MMF), a highly effective immunosuppressant with no known nephrotoxicity, has been shown to provide benefits in preserving long-term renal allograft function relative to azathioprine. For these reasons, MMF has become an integral component of toxicity-sparing maintenance regimens that seek to minimize patient exposure to CNIs and steroids. This paper provides an overview of current strategies for reducing the toxicities associated with these agents, which include both withdrawal and avoidance regimens with or without induction therapy. Data are accumulating that toxicity-sparing regimens involving MMF are safe and decrease the risk of side effects that accompany the use of CNIs and steroids. Future studies will determine how to best implement these regimens in the renal transplant population.

The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation.

The Injury Hypothesis, first published in 1994 and modified several times between 1996 and 2002, holds that the reactive oxygen species-mediated reperfusion injury to allografts initiates and induces the alloimmune response and contributes to alloatherogenesis. Recent experimental and clinical evidence in support of the concept is presented suggesting that (1) reactive oxygen species-mediated allograft injury activates the innate immune system of the donor and recipient; (2) injury-induced putative endogenous ligands of Toll-like receptors (TLRs) of host origin such as heat shock proteins interact with and activate TLR4-bearing dendritic cells that mature and induce the adaptive alloimmune response (acute rejection), and interact with and activate TLR4-bearing vascular cells contributing to the development of alloatherosclerosis (chronic rejection); and (3) TLR4-triggered signaling, involved in the establishment of a reperfusion injury, seems to use myeloid differentiation marker 88-independent, Toll/interleukin-1 receptor domain containing adaptor inducing interferon-beta-dependent pathways that are associated with the maturation of dendritic cells and induction of interferon-inducible genes.

How evolution tells us to induce allotolerance.

Modern immunology, in many ways, is based on 3 major paradigms: the clonal selection theory (Medawar, Burnet; 1953/1959), the pattern recognition theory (Janeway; 1989), and the danger/injury theory (Matzinger, Land; 1994). The last theory holds that any cell stress and tissue injury including allograft injury, via induction of damage-associated molecular patterns, induces immunity including alloimmunity leading to allograft rejection. On the other hand, the concept precludes that "non-self " per se induces immunity as proposed by the two former theories. Today, the danger/injury model has been largely accepted by immunologists, as documented by a steadily increasing number of publications. In particular, overwhelming evidence in support of the correctness of the model has come from recent studies on the gut microbiota representing a huge assemblage of "non-self. " Here, harmless noninjurious commensal microbes are protected by innate immunity-based immune tolerance whereas intestinal injury-causing pathogenic microbes are immunology attacked. The ability of the immune system to discriminate between harmless beneficial "non-self " to induce tolerance and harmful life-threatening "non-self " to induce immunity has apparently emerged during evolution: Protection of innate immunity-controlled beneficial "non-self " (eg, as reflected by microbiotas but also by the fetus of placental mammals) as well as immune defense responses to injuring/injured "non-self " (eg, as reflected by plant resistance to biotic and abiotic stress and allograft rejection in mammals) evolved under pressure across the tree of life, that is, in plants, lower and higher invertebrates as well as lower and higher vertebrates. And evolution tells us why the overall existence of protected microbiotas really makes sense: It is the formation of the "holobiont, " - a metaorganism - that is, the host plus all of its associated microorganisms that - in terms of a strong unit of selection in evolution - provides that kind of fitness to all species on earth to successfully live, survive and reproduce. In other words: "We all evolve, develop, grow, and reproduce as multigenomic ecosystems! Regarding reproduction, another impressive example of active immunologic protection of "nonself " refers to pregnancy in placental mammals that emerged about 400 millions of years ago. Similar to "non-self " microbiotas, pregnancy in placental mammals reflects an evolution-driven phenomenon on the basis of innate immunity-controlled tolerance induction to semiallogeneic non-injuring/non-injured "non-self " aiming to ensure reproduction! Altogether, the lesson learned from evolution of how to avoid allograft rejection is clear: prevent allograft injury to induce allotolerance, in other words: create a "transplant holobiont. ".

The Role of Damage-Associated Molecular Patterns (DAMPs) in Human Diseases: Part II: DAMPs as diagnostics, prognostics and therapeutics in clinical medicine.

This article is the second part of a review that addresses the role of damage-associated molecular patterns (DAMPs) in human diseases by presenting examples of traumatic (systemic inflammatory response syndrome), cardiovascular (myocardial infarction), metabolic (type 2 diabetes mellitus), neurodegenerative (Alzheimer's disease), malignant and infectious diseases. Various DAMPs are involved in the pathogenesis of all these diseases as they activate innate immune machineries including the unfolded protein response and inflammasomes. These subsequently promote sterile autoinflammation accompanied, at least in part, by subsequent adaptive autoimmune processes. This review article discusses the future role of DAMPs in routine practical medicine by highlighting the possibility of harnessing and deploying DAMPs either as biomarkers for the appropriate diagnosis and prognosis of diseases, as therapeutics in the treatment of tumours or as vaccine adjuncts for the prophylaxis of infections. In addition, this article examines the potential for developing strategies aimed at mitigating DAMPs-mediated hyperinflammatory responses, such as those seen in systemic inflammatory response syndrome associated with multiple organ failure.

The Role of Damage-Associated Molecular Patterns in Human Diseases: Part I - Promoting inflammation and immunity.

There is increasing interest by physicians in the impact of the innate immune system on human diseases. In particular, the role of the molecules that initiate and amplify innate immune pathways, namely damage-associated molecular patterns (DAMPs), is of interest as these molecules are involved in the pathogenesis of many human disorders. The first part of this review identifies five classes of cell stress/tissue injury-induced DAMPs that are sensed by various recognition receptor-bearing cells of the innate immune system, thereby mounting inflammation, promoting apoptosis and shaping adaptive immune responses. The DAMPs activate and orchestrate several innate immune machineries, including inflammasomes and the unfolded protein response that synergistically operates to induce inflammatory, metabolic and adaptive immune pathologies. Two examples of autoimmune diseases are discussed as they represent a typical paradigm of the intimate interplay between innate and adaptive immune responses.