Role of Ischemia/Reperfusion and Oxidative Stress in Shock State

1. Introduction

The Shock state (a life-threatening condition caused by inadequate blood flow) is a critical condition produced by an insufficient supply of oxygen and nutrients to the tissues in relation to the tissue metabolic demand [1,2,3]. The pathological state progresses with the deterioration of the function of vital organs such as the brain, heart, kidneys, lungs, liver, and gastrointestinal tract. For instance, reduced perfusion in the kidneys may lead to acute kidney injury, while hypoxia in the brain can result in cognitive impairment or loss of consciousness [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]. The secondary effect is mediated by circulatory failure that will produce inadequate or inappropriate tissue perfusion distribution resulting in systemic cellular hypoxia. Under these critical conditions, the pathophysiological characteristics are driven by inadequate oxygen and metabolic substrate supply, alongside increasing demands for these requirements. This imbalance can result in cellular injury and eventual organ dysfunction [6,15,20,21,22,23,24,25,26]. In parallel, the inability to eliminate metabolites and wastes resulting from energy expenditure, hypoxic adaptation, cellular injury, and cell death can exacerbate the condition, ultimately causing permanent damage. [27,28,29,30,31,32,33]

Understanding any shock state requires recognizing the concept of shock as “inadequate organ and peripheral tissue perfusion” [34,35,36,37,38,39,40,41]. When analyzing ischemia/reperfusion (I/R) lesions, it is important to note that ischemia is defined as “the abrupt blockage of the blood supply that causes an imbalance in the oxygen supply and metabolic nutrients essential for cell survival.” This leads to hypoxia, metabolic disruption, and impaired energy production [26,42,43,44]. The Shock state and the first component of I/R lesions share the same outcome: systemic cellular hypoxia and metabolic failure. Although the mechanisms behind their initiation may differ, both phenomena result in similar detrimental effects across the entire system. [26,41,42,43,44,45,46,47,48,49]

2. Classification and Categorization of Shock State

To understand the process of shock, it is necessary to classify the different types, as they differ in pathological mechanisms and therapeutic approaches. These differences are crucial because they guide the selection of appropriate treatments. For instance, hypovolemic shock caused by acute blood loss requires fluid resuscitation and blood transfusion, whereas septic shock requires antibiotics to target the underlying infection and vasopressors to restore vascular tone [50,51,52,53,54,55]. Shock is currently classified into five types: hypovolemic, distributive, cardiogenic, obstructive, and mixed. Each type has distinct causes and requires specialized management. [56,57,58,59,60]

Hypovolemic shock is the condition where the system presents inadequate organ perfusion caused by loss of intravascular volume [56,61,62].

It can be subclassified into four main categories depending on the mechanics of the lesion, as shown below:

Table 1. Hypovolemic shock categorization and clinical sceneries.

Hypovolemic Shock Categories	Volume Mechanism	Tissue Injury	Clinical Scenario
Hemorrhagic shock	Acute hemorrhage (critical)	No major soft tissue injury	Aortic dissection rupture
Traumatic hemorrhagic shock	Acute hemorrhage (critical)	With major soft tissue injury	Polytrauma
Pure hypovolemic shock	Reduction (critical) of circulating plasma volume (fluid loss) without hemorrhage	No major soft tissue injury	Persistent fever, diarrhea, or vomiting
Traumatic hypovolemic shock	Reduction (critical) of circulating plasma volume (fluid loss) without hemorrhage	With major soft tissue injury	Large surface burns or deep skin lesions

Table 1. Hypovolemic shock categorization and clinical sceneries.

Hypovolemic Shock Categories	Volume Mechanism	Tissue Injury	Clinical Scenario
Hemorrhagic shock	Acute hemorrhage (critical)	No major soft tissue injury	Aortic dissection rupture
Traumatic hemorrhagic shock	Acute hemorrhage (critical)	With major soft tissue injury	Polytrauma
Pure hypovolemic shock	Reduction (critical) of circulating plasma volume (fluid loss) without hemorrhage	No major soft tissue injury	Persistent fever, diarrhea, or vomiting
Traumatic hypovolemic shock	Reduction (critical) of circulating plasma volume (fluid loss) without hemorrhage	With major soft tissue injury	Large surface burns or deep skin lesions

Distributive shock is the critical redistribution of the absolute intravascular volume and, depending on its causes, can be subclassified into four major types: septic (infections), anaphylactic (immune response), neurogenic (acute neurological trauma), and endocrine shock (acute adrenal insufficiency) [3,56,63]. Septic shock is distinct due to its infectious etiology, leading to widespread inflammation and vasodilation triggered by microbial toxins. In contrast, anaphylactic shock results from a severe allergic reaction, where histamine release causes rapid vascular permeability and hypotension. Neurogenic shock involves loss of sympathetic tone, often after spinal cord injury, leading to unopposed parasympathetic activity and bradycardia. Endocrine shock, such as in acute adrenal insufficiency, results from hormonal deficits causing vascular instability. These differences underline the importance of precise identification for targeted management [3,63,64,65].

Cardiogenic shock is the critical reduction of the heart’s pumping capacity where the most common causes are myocardial failure (acute myocardial infarction), cardiac conduction system failure (brady and tachyarrhythmias), and heart valves dysfunctions (acute insufficiency and decompensated stenosis) [56,66,67,68].

Obstructive shock occurs due to obstruction in critical vascular or cardiac structures. It can arise from extracardiac conditions such as aortic dissection, which impede blood flow, or mechanical obstructions affecting the heart, like tumors or hemopericardium. Additionally, issues with afterload or preload may impair venous return or increase resistance, as seen in pneumothorax, hemothorax, pneumopericardium, or hemopericardium. Pulmonary causes, such as pulmonary embolism, can also hinder blood flow in the lungs. Each of these mechanisms results in inadequate cardiac output and systemic perfusion, necessitating targeted interventions [3,56,69,70].

Besides the classification of shock and subclass, there is a categorization of shock severity that involves the ability of the body to compensate. Non-progressive shock, also known as compensated shock, is characterized by the activation of allostatic mechanisms, such as increased heart rate and vasoconstriction, to maintain perfusion to vital organs. Progressive shock occurs when these compensatory mechanisms fail, leading to worsening tissue hypoxia, metabolic acidosis, and organ dysfunction [3,71,72,73,74]. Finally, irreversible shock results in multi-organ dysfunction syndrome (MODS), where tissue damage becomes severe and unresponsive to therapeutic interventions [3,71,72,73,74,75,76,77] In the compensated state, the mechanisms of allostasis (the body’s process of maintaining stability) temporarily adapt to the pathological changes induced by the shock state. During this period, unaffected organs and physiological systems strive to maintain perfusion to vital organs. However, if these adaptations fail, the system transitions into a non-compensatory state, leading to further deterioration and progression of the shock state. [3,71,72,73,74]

3. Progression of Shock State

Independently of the type of shock, the progression will have a stereotyped development, where depending on the ability of the tissues to tolerate the ischemia, the degree of the initial injury, the delay of the initial treatment to containment/eliminate the aggression, the non-injured tissue will start to present lesion or develop permanent damage [3,71,72,73,74]. In the clinical scenario, there is the presence of multiple syndromes that follow the intent of the body to adapt to the aggression (Figure 1). However, if the shock progresses, it will produce deleterious effects on the prognosis of the patient [3,72,73,74,78,79,80].

In the cellular scenario, several events perpetuate the progression of the shock, decreasing the ability of the cells to tolerate the aggression. The micro-verse (cellular neighboring) and macro-verse (organ systems intercommunication) will orchestrate together the death of the cells and the body system failure.

4. The Micro-Verse

In the process of cellular function decay, the principal aggressor is systemic ischemia, which affects all cell populations [81,82,83]. Some groups activate adaptive mechanisms (adrenergic, hormonal, metabolic, and hypoxia-inducible systems) to increase tolerance to ischemic injury [84,85,86,87,88,89,90,91,92,93,94]. Tissues such as skeletal muscle, skin, bone, and hepatocytes exhibit higher tolerance to changes induced by initial injury and systemic ischemia [23,95,96,97,98,99,100,101,102,103,104,105]. In contrast, tissues with lower ischemic tolerance—such as epithelial, endothelial, myocardial cells, neurons, previously injured cells, or those affected by chronic conditions like diabetes, hypertension, cancer, or toxin exposure—are more prone to pathological states such as apoptosis, autophagy, and necrosis [106,107,108,109,110,111,112,113,114,115,116,117,118]. The close interaction between these cellular territories initiates the acute shock state without adequately addressing the subsequent responses triggered by ischemia/reperfusion (I/R) injury [124,125,126,127,128,129,130]. The time of systemic ischemia remains a critical determinant of patient prognosis, as prolonged ischemia can lead to irreversible cellular damage and systemic complications (Figure 2) [124,125,126,127,128,129,130]. Understanding and elucidating the variables involved in the progression of the shock state, particularly those related to I/R injury and its downstream effects, remain a priority to enhance long-term patient outcomes.

5. Adaptative Micro-Verse System During Shock Progression

In the ischemia/reperfusion (I/R) lesion the clinical syndrome known as the Systemic Inflammatory Response Syndrome (SIRS), which reflects the body’s attempt to respond to and adapt to systemic aggression [119,120,121,122,123].

Health systems now employ highly standardized training programs to recognize and treat shock states, significantly reducing the duration of systemic ischemia compared to previous generations [124,125,126,127,128,129]. While these efforts have improved the immediate survival rates, they often focus solely on resolving, there are three key segments of injury: (1) activation of the cellular membrane and metabolic system processes to tolerate intracellular changes induced by the deprivation of energetic substrates (e.g., cytosolic cation influx, oxidative stress, and mitochondrial dysfunction), (2) intercellular signaling and interactions between different cellular groups (neighboring effect) that propagate damage (e.g., endothelial damage, no-reflow phenomenon, and transcriptional reprogramming), and establishment of the I/R lesion, characterized by immune system activation, apoptosis, autophagy, and necrosis. Usually, the extent of injury is confined to the affected organ with arterial occlusion, but in shock states, ischemia affects multiple organs and systems simultaneously [25,26,42,131,132,133]

Several groups of cells experience membrane instability and massive oxidative stress production, amplifying the effects of neighboring cellular responses. Some cell populations will reach the I/R lesion at different time points in an asynchronous pattern, producing distinct clinical symptoms [7,131,132,134,135,136,137]. The cells capable of adapting to the initial insult activate different molecular pathways to tolerate ischemia. One of the most critical regulatory systems is the hypoxia-inducible factor (HIF) pathway, which governs cellular responses to hypoxic stress [138,139,140,141,142,143].

The HIF pathway consists of transcription factors that regulate cellular adaptation, with three major members: HIF-1 (HIF-1α & HIF-1β), HIF-2α, and HIF-3α. The functional dynamics of HIF-1 are complex, as it interacts with other HIF family members in a tissue-specific manner. While HIF-1α and HIF-1β are ubiquitously expressed in all cells, HIF-2α is primarily found in epithelial cells of the lungs and endothelial cells in the carotid body. In contrast, HIF-3α is predominantly expressed in Purkinje cells of the cerebellum and corneal cells [144,145,146,147,148,149,150,151,152,153]. HIF-1α and HIF-2α share approximately 48% sequence homology and can dimerize with HIF-1β to interact with hypoxia response elements (HREs) in DNA, thereby modulating gene transcription. While HIF-1α and HIF-2α enhance gene expression, HIF-3α serves as an inhibitor of HRE-mediated gene transcription [144,145,146,147,148,149,150,151,152,153].

Under hypoxic conditions, HIF-1α is stabilized and phosphorylated by MAPK signaling. It subsequently forms a complex with CBP/p300, which is translocated into the nucleus. There, it dimerizes with HIF-1β [HIF-1α(CBP/p300)/HIF-1β complex] and binds to HREs, initiating the transcription of genes involved in erythropoiesis, iron metabolism, angiogenesis, glucose metabolism, cell proliferation, survival, and apoptosis. The extent of gene expression depends on the specific cell type (e.g., endothelial, myocardial, epithelial, immune, neuronal, skeletal muscle, pluripotent) and the duration of activation (seconds, minutes, or hours of hipoxia-ischemia) [154,155,156,157,158]

In shock states, some cell populations initially respond by shifting metabolism toward oxygen-independent glycolysis, upregulating glucose transporters (GLUT-1 and GLUT-3) and increasing glycolytic enzyme activity to generate ATP and pyruvate. Concurrently, the HIF-1α/CBP/p300/HIF-1β complex enhances the expression of genes such as lactate dehydrogenase A (LDHA), monocarboxylate transporter 4 (MCT4), pyruvate dehydrogenase kinase 1 (PDK1), COX4-2, and mitochondrial protease LONP1. This metabolic shift leads to lactate accumulation (which is subsequently removed via MCT4), inhibition of pyruvate-to-acetyl-CoA conversion (via PDK1-mediated PDH inhibition), attenuation of oxidative phosphorylation, and reduction of excessive mitochondrial ROS and RNS production by enhancing electron transport efficiency (via COX4-2 and LONP1-mediated COX4 downregulation) [159,160,161,162,163,164]

Beyond its metabolic effects, HIF-1α signaling promotes cellular proliferation and survival by inducing the expression of insulin-like growth factor-2 (IGF-2) and transforming growth factor-alpha (TGF-α), alongside activating the MAPK, PI3K, and AMPK pathways. These responses exhibit both local (autocrine) and systemic (endocrine) effects, a phenomenon termed the “neighboring effect.” These mechanisms collectively help keep cells within a “point of safe return”—the threshold before mitochondrial damage becomes irreversible [7,21,22,24,26,42].

However, in some cell populations, or if the shock state persists, the excessive activity of the HIF pathway may lead to maladaptive consequences, including apoptosis, overactivation of the immune system, and upregulation of adrenergic receptors. Clinically, this manifests as arrhythmias and blood pressure dysregulation [165,166,167,168]. Overactive HIF signaling upregulates the expression of apoptosis-related genes, including caspase-3, Fas/Fas-ligand, Bcl-2/adenovirus EIB19, BNip3, and NIX. Additionally, it enhances p53 and p21 signaling, which increases the expression of pro-apoptotic proteins such as Bax, NOXA, PUMA, and PERP, ultimately leading to widespread cellular death and late-stage tissue injury [165,166,167,168].

A key clinical marker of deteriorating HIF-mediated adaptation is oxygen debt, which correlates with increased blood lactate levels. In the clinical setting, elevated lactate is strongly associated with shock progression and poor prognosis [2,165,166,167,168]. The persistence of high lactate levels reflects ongoing ischemic tissue metabolism, increased oxygen consumption by hypoxic tissues, and the inability of systemic perfusion to meet metabolic demands. Monitoring lactate levels provides valuable prognostic information and helps guide therapeutic interventions aimed at mitigating ischemia-reperfusion injury [169,170,171,172].

6. The Macro-Verse

As the shock state progresses and the group of cells capable of tolerating systemic ischemia deteriorates, organs and systems begin to interact in an attempt to sustain overall bodily function [173,174,175,176,177,178]. Several systemic mechanisms are activated, including the adrenergic response, the endocrine system (renin-angiotensin-aldosterone system, RAAS), and the immune system. Initially, these mechanisms work synergistically to maintain minimal perfusion in central circulation, prioritizing vital organs such as the brain, lungs, heart, liver, and kidneys. This is achieved through the release of adrenaline and noradrenaline, which activate adrenergic receptors, the activation of RAAS to regulate vascular tone and fluid balance, and the immune system’s initiation of tissue repair processes. However, as the shock state advances and the number of damaged cells increases, these compensatory mechanisms begin to fail, leading to dysregulated immune responses and pathological outcomes [84,85,86,87,88,89,90,91,92,93,94].

7. Ischemia Phase and Immune System

During the ischemia phase and the progression of the shock state, various cellular mechanisms are activated to increase ischemic tolerance. However, if the ischemic lesion surpasses the system’s compensatory capacity, the immune response shifts from a repair-sustain function to a degradation-destruction state, ultimately modulating cellular apoptosis in the affected organs [84,85,86,87,88,89,90,91,92,93,94].

The immune system undergoes a staged transition during shock progression (Figure 3), consisting of four key phases: (i) Systemic Inflammatory Response Syndrome (SIRS), characterized by widespread immune activation and inflammatory cytokine release; (ii) Compensatory Anti-inflammatory Response Syndrome (CARS), a counter-regulatory mechanism to suppress excessive inflammation and restore immune homeostasis; (iii) Mixed Antagonist Response Syndrome (MARS), where inflammatory and anti-inflammatory processes coexist, leading to immune dysregulation; and (iv) Cardiovascular compromise – Loss of Homeostasis – Apoptosis – Organ Dysfunction (CHAOS), representing a state of profound systemic failure and immune exhaustion (Figure 2) [76,173,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198]. Each of these stages manifests as a progressive adaptation of the immune response to ongoing shock progression, driven by oxidative stress, metabolic disturbances, and continued ischemic injury [76,173,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198].

The activation of the immune system begins with the first hit (the initial insult), where the pathological mechanisms of each shock type and subclass play a role in triggering immune responses. Affected cells upregulate the expression of pattern recognition receptors (PRRs), including Microbe-Associated Molecular Patterns (MAMPs), which are released when the mucosae (such as the skin, eyes, genital tract, or gastrointestinal tract) are disrupted, exposing constitutional microbiota and surrounding pathogens to the systemic circulation [199,200,201,202,203,204]. Damage-Associated Molecular Patterns (DAMPs) originate from locally traumatized tissue, while Pathogen-Associated Molecular Patterns (PAMPs) are characteristic of septic shock, where microbial invasion drives immune activation [176,205,206,207,208]. These signals collectively stimulate the production of key inflammatory cytokines, including IL-1, IL-6, IL-17, TNF-alpha, and IL-10, while also activating NF-κB signaling [204,209,210,211,212,213].

Initially, immune activity aims to contain damage and facilitate tissue repair through the SIRS mechanism. However, if the injury is extensive or the shock state progresses, excessive immune activation can lead to a dysregulated response. This results in the transition from SIRS to CARS, a counter-regulatory mechanism designed to suppress excessive inflammation and restore homeostasis (Table 2) [76,173,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198].

As the progression or extension of damage in shock continues, the interaction between the SIRS and CARS responses induces the state of MARS, representing a dynamic balance between these opposing immune responses (Figure 2). Clinically, this phase corresponds to the compensated state of shock, where all organs and tissues remain in a precarious equilibrium that can only persist for a limited period before reaching a critical threshold of failure. If this threshold is exceeded, the system may shift towards either of two pathological overlays: (i) SIRS dominance over MARS, which exacerbates tissue destruction and coagulation activity mediated by the immune system (Figure 3), or (ii) CARS dominance over SIRS, increasing susceptibility to infections and delaying tissue repair. In both scenarios, the system ultimately deteriorates into CHAOS, leading to multi-organ dysfunction and systemic failure (Figure 3) [76,173,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198].

The immune components play a crucial role in regulating various clinical syndromes, particularly as shock progresses (Figure 3). Understanding the functional dynamics of these cellular components is essential for modulating immune responses and mitigating pathological outcomes.

8. IL-1 Signaling Pathway: Activation and Inhibition

The interleukin-1 receptor (IL-1R) family consists of ten members classified into four subgroups: ligand-binding receptors (IL-1R1, IL-1R2, IL-1R4, IL-1R5, and IL-1R6), accessory proteins (IL-1R3 and IL-1R7), negative regulatory receptors (IL-1R2, IL-1R8, and IL-1R8BP), and members with unknown functions (IL-1R9 and IL-1R10) [214,215,216,217,218,219,220,221,222,223]. These receptors play a critical role in immune regulation by interacting with Toll-like receptors (TLRs) through the Toll/interleukin-1 receptor (TIR) domain, which is essential for recruiting and differentiating immune cells. Furthermore, the TIR domain shares homology with MyD88, a key adaptor molecule involved in immune signaling pathways (Figure 4) [214,215,216,217,218,219,220,221,222,223,224].

IL-1R1 activation occurs when it forms a complex with accessory proteins IL-1R3 and IL-1R7, allowing the binding of ligands such as IL-1α, IL-1β, or IL-38. The downstream effects of IL-1R activation depend on the target cell type and include the induction of inflammatory cytokines, amplifying immune responses [214,215,216,217,218,219,220,221,222,223,224,225]; the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), contributing to cellular damage [221,226,227,228,229]; increased prostaglandin synthesis, promoting inflammatory mediator production [220,230,231,232,233,234]; proteolytic enzyme activation, which facilitates extracellular matrix degradation and tissue remodeling [235,236,237,238,239,240,241,242,243,244,245,246,247,248,249]; and immune system modulation, enhancing adaptive immune responses through T cell expansion and Th17 differentiation [250,251,252,253,254,255].

At the intracellular level, IL-1R signaling begins when a ligand, such as IL-1β, binds to IL-1R1, forming a receptor-ligand complex with IL-1R3. This interaction recruits MyD88 via the TIR domain, leading to the activation of two major signaling cascades: the nuclear factor kappa B (NF-κB) pathway, which drives the transcription of proinflammatory cytokines [214,215,216,217,218,219,220,221,222,223,224,225], and the mitogen-activated protein kinase (MAPK) pathway, which regulates inflammatory mediator production and cellular stress responses [256,257,258,259,260]. While these pathways are essential for responding to infections and tissue injury, their uncontrolled activation can result in chronic inflammation, tissue damage, and autoimmune disorders [261,262,263].

Overactivation of IL-1R signaling contributes to oxidative stress by promoting excessive ROS and RNS production. Mitochondria are the primary sources of ROS, while NADPH oxidase plays a critical role in generating superoxide radicals [264,265,266,267,268,269,270,271]. This oxidative imbalance leads to mitochondrial dysfunction, impairing energy production and promoting apoptosis [264,265,266,267,268,269,270,271]; endoplasmic reticulum (ER) stress, disrupting protein folding and triggering the unfolded protein response [225,272,273,274,275,276]; lysosomal damage, resulting in the release of hydrolytic enzymes that contribute to cell death; and DNA damage, leading to genotoxic stress, mutations, and cellular senescence [277,278,279,280,281].

Certain cell types are particularly susceptible to excessive IL-1 signaling and oxidative stress. Immune cells such as macrophages, neutrophils, and dendritic cells may become hyperactivated, leading to a state of uncontrolled inflammation [282,283,284,285,286,287]. Endothelial cells experience increased vascular permeability and dysfunction, contributing to systemic inflammation [288,289,290,291,292,293]. Neurons are particularly vulnerable to chronic inflammation and oxidative damage, which have been implicated in neurodegenerative diseases [294,295,296,297]. Cardiomyocytes also suffer from oxidative stress-induced injury, exacerbating heart failure progression [298,299,300,301,302].

In clinical conditions such as shock and ischemia-reperfusion injury (IRI), IL-1R activation plays a pivotal role in tissue damage. During shock, excessive cytokine production and oxidative stress drive systemic inflammation and multi-organ dysfunction [303,304,305,306,307]. In ischemia, oxygen deprivation triggers metabolic distress, while reperfusion further exacerbates injury through a surge in ROS production and inflammatory mediators c [307,308,309,310,311].

To counteract excessive IL-1 signaling, the immune system employs regulatory mechanisms such as soluble and decoy receptors that sequester IL-1 ligands. Among them, sIL-1R2 and sIL-1R3 function as competitive inhibitors by binding IL-1 ligands without initiating downstream signaling [312,313,314]. However, in prolonged shock or ischemic conditions, excessive expression of decoy receptors can lead to immunosuppression, increasing susceptibility to secondary infections and impairing recovery [232,282,291,304,315,316,317]. This phenomenon is particularly evident in post-cardiac arrest syndrome and septic shock, where dysregulated IL-1 signaling has been associated with poor clinical outcomes [318,319,320,321,322,323].

Maintaining a balanced IL-1 signaling response is crucial for immune homeostasis and for preventing excessive inflammation. Future research should focus on developing therapeutic interventions targeting this pathway to mitigate tissue damage in inflammatory and ischemic conditions.

9. IL-6 and TNF-α Pathways in Shock Progression

The IL-6 family consists of 10 ligands and 9 receptors, with signaling mediated by the gp130 receptor, which is ubiquitously expressed in all cells [324,325,326,327,328,329,330,331]. The pathway involves Janus kinase (JAK), signal transducer and activator of transcription factor 3 (STAT3), and JAK-SHP-2-mitogen-activated protein kinase (MAPK). IL-6 interacts with IL-6Rα (membrane-bound and soluble forms) and recruits gp130 to initiate intracellular signaling. This signaling cascade modulates inflammation, endothelial activation, hepatic acute-phase protein production, and immune cell differentiation [332,333,334,335,336,337,338].

IL-6 signaling can contribute to oxidative stress by activating intracellular pathways that lead to increased production of reactive oxygen species (ROS). The activation of STAT3 and MAPK pathways has been shown to enhance mitochondrial ROS production, leading to oxidative damage and further perpetuation of inflammatory responses [339,340,341,342,343]. Additionally, IL-6 can induce the expression of NADPH oxidase (NOX) enzymes, which catalyze the production of ROS, exacerbating oxidative stress and promoting endothelial dysfunction [344,345,346,347].

Excessive IL-6 signaling leads to chronic inflammation, tissue damage, and immune exhaustion, whereas inadequate signaling results in impaired immune responses and susceptibility to infections [348,349,350].

The TNF family includes at least 18 ligands and 29 receptors, mediating inflammation, apoptosis, and immune system regulation. TNF-α interacts with TNFR1 and TNFR2, leading to differential downstream signaling. TNFR1 activation predominantly results in proinflammatory and apoptotic pathways, while TNFR2 signaling is associated with immune modulation and tissue repair [351,352,353,354,355].

In early shock response, TNF-α/TNFR1 and TNF-α/TNFR2 drive macrophage activation, monocyte recruitment, and cytokine amplification [356,357,358,359,360]. While essential in initial host defense, excessive TNF-α signaling contributes to endothelial dysfunction, tissue damage, and systemic inflammation characteristic of septic shock, ischemia-reperfusion injury, and multiple organ dysfunction syndrome (MODS) [361,362,363,364,365,366,367]. Additionally, TNF-α induces oxidative stress by stimulating mitochondrial dysfunction and increasing reactive oxygen species (ROS) production, exacerbating cellular damage [368,369,370,371,372,373].

Therapeutic inhibition of TNF pathways is widely explored in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, yet excessive downregulation in critically ill patients can impair immune defense and increase susceptibility to secondary infections [374,375,376,377,378,379,380].

10. Integration of IL-1, IL-6, and TNF-α in Inflammatory Waves

Under synergistic action, IL-1, IL-6, and TNF-α drive the initial inflammatory wave aimed at damage containment and repair (Figure 4). This wave is characterized by i)Pro-inflammatory actions: Rapid cytokine production, immune cell recruitment, and activation of tissue repair mechanisms. ii)Self-modulatory mechanisms: Simultaneous release of regulatory molecules, including decoy receptors, to limit overactivation.

11. Regulation and Pathophysiological Implications

Regulation of these pathways is critical to maintaining immune balance. Excessive activation, as seen in chronic inflammation or severe injuries, can lead to tissue damage and autoimmune conditions. Conversely, overexpression of regulatory mechanisms (e.g., decoy receptors) may result in immunosuppression, especially in prolonged shock states. This duality underscores the importance of i)Therapeutic targeting of pathways (e.g., IL-1 receptor antagonists, JAK inhibitors). ii) Monitoring cytokine levels to predict progression from pro-inflammatory to regulatory phases.

The balance between IL-6, TNF-α, and IL-1-driven inflammation determines shock progression. Uncontrolled proinflammatory signaling leads to tissue damage, while excessive counter-regulation via soluble cytokine receptors or anti-inflammatory mediators may cause immune paralysis and secondary infections [381,382,383,384,385,386]. Understanding these dynamics is crucial for developing targeted immunomodulatory therapies in critical care medicine.

12. CTLA-4 and PD-1: Immune Checkpoint Pathways

CTLA-4 (Cytotoxic T-lymphocyte antigen 4) and PD-1 (Programmed cell death protein-1) are key regulators of immune response suppression and inflammation control, and those can by overactivated or inhibited by several mechanism (Table 3) [387,388,389,390,391,392,393,394,395,396,397]. They function as immune checkpoints that prevent excessive immune activation and protect against autoimmunity, but in anomalous conditions can have negative contribution in the survival of a patient with shock progression state.

13. CTLA-4 and PD-1 Signaling Mechanisms

CTLA-4 competes with CD28 for B7 ligands (CD80/CD86), suppressing T-cell activation by limiting costimulatory signaling. It recruits phosphatases such as SHP-2 and PP2A, which dephosphorylate key signaling proteins like CD3 and ZAP70, preventing full T-cell activation (Figure 5). The dominance of its activation is upregulated in the presence of excessive immune response [398,399,400,401,402].

PD-1 is expressed on activated T-cells, B cells, and monocytes. When engaged with its ligands, PD-L1 or PD-L2, PD-1 recruits SHP-1 and SHP-2 to dephosphorylate ZAP-70, blocking downstream activation of PI3K-Akt and Ras-MEK-ERK pathways. This results in inhibition of T-cell proliferation and cytokine release [403,404,405,406,407,408].

14. Integration Inflammatory/Anti-inflammatory Signaling

The signaling pathways of IL-1, IL-6, and TNF-α play a central role in activating the immune system and regulating inflammatory responses. However, immune checkpoint mechanisms such as CTLA-4 and PD-1 modulate these signals to prevent excessive and potentially harmful immune reactions [393,394,396,409,410,411,412,413].

CTLA-4 exerts its regulatory effect by dampening IL-1-driven inflammatory responses. It achieves this by inhibiting early T-cell activation, a key process in the amplification of IL-1-mediated inflammation. By blocking this initial activation, CTLA-4 limits the production of pro-inflammatory mediators, thereby reducing tissue damage associated with exaggerated immune responses [393,394,396,409,410,411,412,413]

On the other hand, the PD-1 pathway plays a crucial role in modulating IL-6 signaling. PD-1 activation inhibits IL-6-induced STAT3 activation, leading to a reduction in inflammatory cytokine production and a lower propensity for cytokine storms. This mechanism is essential in preventing uncontrolled systemic inflammation, which can result in multi-organ dysfunction and severe tissue damage [393,394,396,409,410,411,412,413].

Furthermore, both CTLA-4 and PD-1 work together to counteract TNF-α signaling. TNF-α is a key cytokine in inflammation and immune activation, but its excessive activity can lead to tissue damage and immune exhaustion. The regulation of TNF-α by these immune checkpoint pathways helps maintain a balance between an effective immune response against pathogens and the prevention of excessive inflammation or autoimmunity [393,394,396,409,410,411,412,413].

Thus, immune checkpoints CTLA-4 and PD-1 play essential roles in maintaining immune homeostasis, preventing excessive inflammatory responses that could compromise tissue integrity and organ function.

15. Oxidative Stress and Shock States

In conditions like ischemia-reperfusion injury and shock, immune checkpoint dysregulation exacerbates oxidative stress and tissue damage [103,368,414,415,416,417]. Oxidative stress plays a critical role throughout the entire pathophysiology of shock, from the initial insult to the progression of the shock state and the establishment of ischemia-reperfusion (I/R) injury. Redox signaling is deeply involved in this process, and even after the resolution of shock, oxidative stress remains active, influencing either recovery or progression into CHAOS [415,418,419,420,421]. Under physiological conditions, oxidative stress is essential for proper cellular function, regulating various signaling pathways [422,423,424,425]. However, in the shock state, oxidative stress production becomes overwhelming due to the extent of cell damage from the initial insult, systemic ischemia, immune system activation, and the massive release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during reperfusion [103,368,414,415,416,417,426]. The oxidative burst not only impacts injured cells but also affects non-damaged and repairing cells, amplifying systemic dysfunction.

Although oxidative stress is necessary for cellular function at a low level, its functional threshold is very narrow. Any perturbation can enhance its activity and induce an imbalance, although the body possesses enzymatic and non-enzymatic mechanisms to regulate oxidative homeostasis [422,423,424,425]. In a clinical setting, patients typically maintain an oxidative balance, fluctuating within normal limits. However, certain populations, including individuals with diabetes, hypertension, dyslipidemia, and cancer, often live under chronic oxidative stress conditions, making them particularly vulnerable to oxidative stress-induced injury [427,428,429,430,431,432].

In shock states, we propose five major factors that could determine the extent of oxidative stress-mediated injury: the degree of cellular damage during the first insult, the level of immune system activation, the impact of I/R injury, the presence of pre-existing pathological conditions, and the basal oxidative stress levels of the patient. If all five components are severe or persist over prolonged periods, oxidative stress leads to extensive cellular dysfunction, affecting survival and worsening the prognosis of shock patients. While some tissues exhibit higher ischemic tolerance, immune and endothelial cells are major ROS and RNS producers [419,433,434,435,436,437]. Furthermore, highly metabolically active cells contribute significantly to the oxidative burden.

The presence of oxidative stress in shock states serves a dual role in regulating inflammation. On one hand, it promotes the activation of proinflammatory pathways. ROS and RNS activate NF-κB by degrading its inhibitor, IκB, leading to the upregulation of inflammatory cytokines such as IL-1, IL-6, and TNF-α [427,438,439,440,441,442,443]. These cytokines further amplify oxidative stress by inducing NADPH oxidase activation in macrophages and neutrophils. Additionally, ROS stimulate the NLRP3 inflammasome, triggering caspase-1 activation and the maturation of IL-1β and IL-18 [427,438,439,440,441,442,443]. This process creates a self-sustaining loop in which oxidative stress perpetuates inflammation. Moreover, excessive ROS and RNS production induce immunogenic cell death mechanisms, such as necroptosis and pyroptosis, causing the release of damage-associated molecular patterns (DAMPs), including HMGB1, ATP, and mitochondrial DNA. These DAMPs activate toll-like receptors (TLRs) and pattern recognition receptors (PRRs), further amplifying the inflammatory response [206,444,445,446,447,448].

On the other hand, oxidative stress also suppresses mechanisms that regulate inflammation, thereby preventing the resolution of immune activation. One of the primary mechanisms of this suppression is the disruption of PD-1 and CTLA-4 regulatory functions [449,450,451,452]. ROS and RNS impair the expression and function of these immune checkpoint proteins, reducing their ability to suppress immune activation. PD-1 normally inhibits T-cell activation by recruiting SHP-1 and SHP-2, but oxidative stress inactivates these phosphatases, allowing unchecked inflammation to persist. Additionally, oxidative stress inhibits IL-10 and TGF-β production, two critical cytokines required for inflammation resolution. The suppression of IL-10 expression in M2 macrophages and dendritic cells contributes to chronic inflammation, further exacerbating tissue damage [453,454,455,456,457]

Oxidative stress also alters the balance between regulatory T-cells (Tregs) and Th17 cells, which play an essential role in immune homeostasis. Under normal conditions, Tregs function to suppress excessive immune activation. However, ROS and RNS favor Th17 differentiation by activating STAT3 and RORγT, leading to increased inflammation [458,459,460,461]. Simultaneously, oxidative stress destabilizes Foxp3, a key transcription factor required for Treg differentiation, further tipping the balance toward proinflammatory responses. The resulting immune dysregulation can contribute to persistent inflammation, tissue destruction, and increased susceptibility to secondary infections [462,463,464,465,466].

Ischemia-reperfusion injury introduces an additional layer of complexity to the oxidative stress response. During the ischemic phase, hypoxia induces HIF-1α, which upregulates inflammatory genes and promotes anaerobic metabolism [161,467,468,469,470]. This metabolic shift leads to mitochondrial damage, releasing cytochrome C and mitochondrial DNA, which activate PRRs and amplify inflammation. Upon reperfusion, a massive oxidative burst occurs as oxygen re-enters the ischemic tissues, leading to mitochondrial ROS overproduction. This sudden influx of ROS triggers NF-κB activation and NLRP3 inflammasome stimulation, perpetuating a self-sustaining inflammatory cycle [471,472,473].

The interplay between oxidative stress, dysregulated inflammation, and ischemia-reperfusion injury has significant clinical implications (Table 4). Excessive ROS and RNS production contribute to multi-organ dysfunction syndrome (MODS), endothelial damage, and coagulopathy. Uncontrolled activation of NF-κB and inflammasomes leads to cytokine storm development in septic shock. Loss of PD-1 and CTLA-4 function results in persistent immune activation and tissue destruction. Disruption of the Treg/Th17 balance fosters chronic inflammation and increases the risk of opportunistic infections. Furthermore, reperfusion-induced oxidative overload worsens ischemia-reperfusion injury and increases patient mortality [474,475,476].

16. Conclusion

Given the profound role of oxidative stress in the pathophysiology of shock, therapeutic strategies aimed at reducing ROS and RNS production hold promise for improving clinical outcomes. Potential interventions include NF-κB inhibition using antioxidants such as N-acetylcysteine and flavonoids, modulation of the NLRP3 inflammasome using pharmacologic inhibitors like MCC950, reactivation of PD-1 and CTLA-4 pathways to control excessive immune activation, targeting mitochondrial ROS production with agents such as Mitochondria-targeted antioxidant agents to prevent reperfusion injury, and restoring the Treg/Th17 balance through therapies that modulate STAT3 and Foxp3 expression.

Understanding the interplay between oxidative stress, inflammation, and ischemia-reperfusion injury provides insight into novel treatment approaches for managing shock states. By targeting oxidative stress-mediated mechanisms, clinicians may be able to mitigate excessive inflammation, reduce tissue damage, and improve overall patient survival. Further research into these therapeutic avenues may lead to the development of effective interventions that balance immune control while preserving essential inflammatory responses necessary for tissue repair and recovery.