The immune system is an evolutionary hallmark of higher organisms that defends the host against invading pathogens and exogenous infections. This defense includes the recruitment of immune cells to ...the site of infection and the initiation of an inflammatory response to contain and eliminate pathogens. However, an inflammatory response may also be triggered by noninfectious stimuli such as major surgery, and, in case of an overshooting, still not comprehensively understood reaction, lead to tissue destruction and organ dysfunction. Unfortunately, in some cases, the immune system may not effectively distinguish between stimuli elicited by major surgery, which ideally should only require a modest inflammatory response, and those elicited by trauma or pathogenic infection. Surgical procedures thus represent a potential trigger for systemic inflammation that causes the secretion of proinflammatory cytokines, endothelial dysfunction, glycocalyx damage, activation of neutrophils, and ultimately tissue and multisystem organ destruction. In this review, we discuss and summarize currently available mechanistic knowledge on surgery-associated systemic inflammation, demarcation toward other inflammatory complications, and possible therapeutic options. These options depend on uncovering the underlying mechanisms and could include pharmacologic agents, remote ischemic preconditioning protocols, cytokine blockade or clearance, and optimization of surgical procedures, anesthetic regimens, and perioperative inflammatory diagnostic assessment. Currently, a large gap between basic science and clinically confirmed data exists due to a limited evidence base of translational studies. We thus summarize important steps toward the understanding of the precise time- and space-regulated processes in systemic perioperative inflammation.
Platelets are most often recognized for their crucial role in the control of acute hemorrhage. However, current research has greatly expanded the appreciation of platelets beyond their contribution ...to primary hemostasis, indicating that platelets also actively participate in leukocyte recruitment and the regulation of the host defense in response to exogenous pathogens and sterile injury. Early recruitment of leukocytes, especially neutrophils, is the evolutionary stronghold of the innate immune response to successfully control exogenous infections. Platelets have been shown to physically interact with different leukocyte subsets during inflammatory processes. This interaction holds far-reaching implications for the leukocyte recruitment into peripheral tissues as well as the regulation of leukocyte cell autonomous functions, including the formation and liberation of neutrophil extracellular traps. These functions critically depend on the interaction of platelets with leukocytes. The host immune response and leukocyte recruitment must be tightly regulated to avoid excessive tissue and organ damage and to avoid chronification of inflammation. Thus, platelet-leukocyte interactions and the resulting leukocyte activation and recruitment also underlies tight regulation by several inherited feedback mechanisms to limit the extend of vascular inflammation and to protect the host from collateral damage caused by overshooting immune system activation. After the acute inflammatory phase has been overcome the host defense response must eventually be terminated to allow for resolution from inflammation and restoration of tissue and organ function. Besides their essential role for leukocyte recruitment and the initiation and propagation of vascular inflammation, platelets have lately also been implicated in the resolution process. Here, their contribution to phagocyte clearance, T cell recruitment and macrophage reprogramming is also of outmost importance. This review will focus on the role of platelets in leukocyte recruitment during the initiation of the host defense and we will also discuss the participation of platelets in the resolution process after acute inflammation.
Surgery and other invasive procedures, which are routinely performed during general anesthesia, may induce an inflammatory response in the patient. This inflammatory response is an inherent answer of ...the body to the intervention and can be both beneficial and potentially harmful. The immune system represents a unique evolutionary achievement equipping higher organisms with an effective defense mechanism against exogenous pathogens. However, not only bacteria might evoke an immune response but also other noninfectious stimuli like the surgical trauma or mechanical ventilation may induce an inflammatory response of varying degree. In these cases, the immune system activation is not always beneficial for the patients and might carry the risk of concomitant, harmful effects on host cells, tissues, or even whole organ systems. Research over the past decades has contributed substantial information in which ways surgical patients may be affected by inflammatory reactions. Modulations of the patient's immune system may be evoked by the use of anesthetic agents, the nature of surgical trauma and the use of any supportive therapy during the perioperative period. The effects on the patient may be manifold, including various proinflammatory effects. This review focuses on the causes and effects of inflammation in the perioperative period. In addition, we also highlight possible approaches by which inflammation in the perioperative may be modulated in the future.
Sepsis is a severe critical illness syndrome that arises from infectious insults. While the host immune system is generally beneficial, an overshooting and unregulated immune response can cause ...serious organ tissue injury. During sepsis, systemic hypotension, disturbed perfusion of the microcirculation, and direct tissue-toxicity caused by inflammatory immune reaction can occur and contribute to organ failure. The failure of two or more vital organ systems is termed multi-organ dysfunction syndrome (MODS) and resembles a very critical condition associated with high morbidity and mortality. Importantly, no specific treatment strategy exists to efficiently prevent the development of MODS during sepsis. In this review, we aim to identify the relevant molecular immunological pathways involved in the pathogenesis of MODS during sepsis. We believe that a detailed understanding of this mechanism is necessary for the development of new treatment approaches for septic patients. In particular, knowledge of the endogenous regulators keeping the balance between necessary immune system activation to combat infections and prevention of host tissue damage would greatly improve the chances for the development of effective interventions.
Kidney disease is a known risk factor for poor outcomes of COVID-19 and many other serious infections. Conversely, infection is the second most common cause of death in patients with kidney disease. ...However, little is known about the underlying secondary immunodeficiency related to kidney disease (SIDKD). In contrast to cardiovascular disease related to kidney disease, which has triggered countless epidemiologic, clinical, and experimental research activities or interventional trials, investments in tracing, understanding, and therapeutically targeting SIDKD have been sparse. As a call for more awareness of SIDKD as an imminent unmet medical need that requires rigorous research activities at all levels, we review the epidemiology of SIDKD and the numerous aspects of the abnormal immunophenotype of patients with kidney disease. We propose a definition of SIDKD and discuss the pathogenic mechanisms of SIDKD known thus far, including more recent insights into the unexpected immunoregulatory roles of elevated levels of FGF23 and hyperuricemia and shifts in the secretome of the intestinal microbiota in kidney disease. As an ultimate goal, we should aim to develop therapeutics that can reduce mortality due to infections in patients with kidney disease by normalizing host defense to pathogens and immune responses to vaccines.
There is emerging evidence that neutrophil extracellular traps (NETs) play important roles in inflammatory processes. Here we report that neutrophils have to be simultaneously activated by ...integrin-mediated outside-in– and G-protein–coupled receptor (GPCR) signaling to induce NET formation in acute lung injury (ALI), which is associated with a high mortality rate in critically ill patients. NETs consist of decondensed chromatin decorated with granular and cytosolic proteins and they can trap extracellular pathogens. The prerequisite for NET formation is the activation of neutrophils and the release of their DNA. In a neutrophil- and platelet-dependent mouse model of ventilator-induced lung injury (VILI), NETs were found in the lung microvasculature, and circulating NET components increased in the plasma. In this model, blocking integrin-mediated outside-in or either GPCR-signaling or heteromerization of platelet chemokines decreased NET formation and lung injury. Targeting NET components by DNAse1 application or neutrophil elastase–deficient mice protected mice from ALI, whereas DNase1−/−/Trap1m/m mice had an aggravated ALI, suggesting that NETs directly influence the severity of ALI. These data suggest that NETs form in the lungs during VILI, contribute to the disease process, and thus may be a promising new direction for the treatment of ALI.
•NET formation is required for neutrophil recruitment during sterile inflammation.•Platelet-induced NET formation requires stimulation of neutrophils by platelet chemokines and outside-in signaling via the integrin Mac-1.
The innate immune response to bacterial infections requires the interaction of neutrophils and platelets. Here, we show that a multistep reciprocal crosstalk exists between these two cell types, ...ultimately facilitating neutrophil influx into the lung to eliminate infections. Activated platelets adhere to intravascular neutrophils through P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1)-mediated binding, a primary interaction that allows platelets glycoprotein Ibα (GPIbα)-induced generation of neutrophil-derived extracellular vesicles (EV). EV production is directed by exocytosis and allows shuttling of arachidonic acid into platelets. EVs are then specifically internalized into platelets in a Mac1-dependent fashion, and relocated into intracellular compartments enriched in cyclooxygenase1 (Cox1), an enzyme processing arachidonic acid to synthesize thromboxane A
(TxA
). Finally, platelet-derived-TxA
elicits a full neutrophil response by inducing the endothelial expression of ICAM-1, intravascular crawling, and extravasation. We conclude that critical substrate-enzyme pairs are compartmentalized in neutrophils and platelets during steady state limiting non-specific inflammation, but bacterial infection triggers regulated EV shuttling resulting in robust inflammation and pathogen clearance.
Platelets are well characterized for their indispensable role in primary hemostasis to control hemorrhage. Research over the past years has provided a substantial body of evidence demonstrating that ...platelets also participate in host innate immunity. The surface expression of pattern recognition receptors, such as TLR2 and TLR4, provides platelets with the ability to sense bacterial products in their environment. Platelet α-granules contain microbicidal proteins, chemokines and growth factors, which upon release may directly engage pathogens and/or contribute to inflammatory signaling. Additionally, platelet interactions with neutrophils enhance neutrophil activation and are often crucial to induce a sufficient immune response. In particular, platelets can activate neutrophils to form neutrophil extracellular traps (NETs). This specific neutrophil effector function is characterized by neutrophils expelling chromatin fibres decorated with histones and antimicrobial proteins into the extracellular space where they serve to trap and kill pathogens. Until now, the mechanisms and signaling pathways between platelets and neutrophils inducing NET formation are still not fully characterized. NETs were also detected in thrombotic lesions in several disease backgrounds, pointing towards a role as an interface between neutrophils, platelets and thrombosis, also known as immunothrombosis. The negatively charged DNA within NETs provides a procoagulant surface, and in particular NET-derived proteins may directly activate platelets. In light of the current COVID-19 pandemic, the topic of immunothrombosis has become more relevant than ever, as a majority of COVID-19 patients display thrombi in the lung capillaries and other vascular beds. Furthermore, NETs can be found in the lung and other tissues and are associated with an increased mortality. Here, virus infiltration may lead to a cytokine storm that potently activates neutrophils and leads to massive neutrophil infiltration into the lung and NET formation. The resulting NETs presumably activate platelets and coagulation factors, further contributing to the subsequent emergence of microthrombi in pulmonary capillaries. In this review, we will discuss the interplay between platelets and NETs and the potential of this alliance to influence the course of inflammatory diseases. A better understanding of the underlying molecular mechanisms and the identification of treatment targets is of utmost importance to increase patients’ survival and improve the clinical outcome.
Difficulties in prediction and early identification of (acute kidney injury) AKI have hindered the ability to develop preventive and therapeutic measures for this syndrome. We tested the hypothesis ...that a urine test measuring insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in acute kidney injury (AKI), could predict AKI in cardiac surgery patients.
We studied 50 patients at high risk for AKI undergoing cardiac surgery with cardiopulmonary bypass (CPB). Serial urine samples were analyzed for TIMP-2*IGFBP7 concentrations. The primary outcome measure was AKI as defined by international consensus criteria following surgery. Furthermore, we investigated whether urine TIMP-2*IGFBP7 could predict renal recovery from AKI prior to hospital discharge.
26 patients (52%) developed AKI. Diagnosis based on serum creatinine and/or oliguria did not occur until 1-3 days after CPB. In contrast, urine concentration of TIMP-2*IGFBP7 rose from a mean of 0.49 (SE 0.24) at baseline to 1.51 (SE 0.57) 4 h after CPB in patients who developed AKI. The maximum urinary TIMP-2*IGFBP7 concentration achieved in the first 24 hours following surgery (composite time point) demonstrated an area under the receiver-operating characteristic curve of 0.84. Sensitivity was 0.92, and specificity was 0.81 for a cutoff value of 0.50. The decline in urinary TIMP-2*IGFBP7 values was the strongest predictor for renal recovery.
Urinary TIMP-2*IGFBP7 serves as a sensitive and specific biomarker to predict AKI early after cardiac surgery and to predict renal recovery.
www.germanctr.de/, DRKS-ID: DRKS00005062.
The availability of handheld, noninvasive sublingual video-microscopes allows for visualization of the microcirculation in critically ill patients. Recent studies demonstrate that reduced numbers of ...blood-perfused microvessels and increased penetration of erythrocytes into the endothelial glycocalyx are essential components of microvascular dysfunction. The aim of this study was to identify novel microvascular variables to determine the level of microvascular dysfunction in sepsis and its relationship with clinical variables.
This observational, prospective, cross-sectional study included 51 participants, of which 34 critically ill sepsis patients were recruited from intensive care units of a university hospital. Seventeen healthy volunteers served as controls. All participants underwent sublingual videomicroscopy by sidestream darkfield imaging. A new developed version of the Glycocheck™ software was used to quantify vascular density, perfused boundary region (PBR-an inverse variable of endothelial glycocalyx dimensions), red blood cell (RBC) velocity, RBC content, and blood flow in sublingual microvessels with diameters between 4 and 25 µm.
A detailed analysis of adjacent diameter classes (1 µm each) of vessels between 4 and 25 µm revealed a severe reduction of vascular density in very small capillaries (5-7 µm), which correlated with markers of sepsis severity. Analysis of RBC velocity (V
) revealed a strong dependency between capillary and feed vessel V
in sepsis patients (R
= 0.63, p < 0.0001) but not in healthy controls (R
= 0.04, p = 0.43), indicating impaired capillary (de-)recruitment in sepsis. This finding enabled the calculation of capillary recruitment and dynamic capillary blood volume (CBV
). Moreover, adjustment of PBR to feed vessel V
further improved discrimination between sepsis patients and controls by about 50%. By combining these dynamic microvascular and glycocalyx variables, we developed the microvascular health score (MVHS
™), which decreased from 7.4 4.6-8.7 in controls to 1.8 1.4-2.7 in sepsis patients (p < 0.0001) and correlated with sepsis severity.
We introduce new important diameter-specific quantification and differentiated analysis of RBC kinetics, a key to understand microvascular dysfunction in sepsis. MVHS
, which has a broad bandwidth to detect microvascular (dys-) function, might serve as a valuable tool to detect microvascular impairment in critically ill patients.
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