Layout 1 Oxy-inflammation in hyperbaric oxygen therapy applications Eur J Transl Myol 35 (1) 12783, 2025 doi: 10.4081/ejtm.2025.12783 Oxygen (O2) comprises a third of human body mass, it represents an essential component of macromolecules such as proteins, carbohydrates, lipids and nucleotides and the major constituent of inorganic compounds of animal shells, teeth and bones. Among hospitalized patients, O2 is the most prescribed drug1 used to treat acute/emergent diseases or chronic pathological conditions such as Chronic Obstructive Pulmonary Diseases (COPD) cystic fibrosis, emphysema and Obstructive Sleep Apnea Syndrome (OSAS). Furthermore, high O2 fraction (fiO2) gas mixtures are administrated to anesthetized patients in order to avoid hypoxemia that can impair capability of the lungs to oxygenate blood because of the negative effects of anesthetics on the pulmonary function. At normobaric pressure, O2 is delivered through nasal cannula, face mask, or endotracheal intubation while, at hyperbaric pressure, using a hyperbaric chamber. A hyperbaric chamber consistsofa pressure vessel and a compressed breathing gas supply which may be used to regulate the internal pressure. The chamber delivers 100% O2 to the patients following predetermined tablesand monitored by trained personnel. Hyperbaric Oxygen Therapy (HBOT)is a non-invasive O2 delivery method that induces systemic hyperoxia. HBO2 therapy is based on the increase of inspired fiO2 combined with elevation of partial O2 pressure (pO2). 2 Typically, O2 is administrated between 1.5 and 3.0 ATA for periods ranged from 60 to 120 min depending on the clinical pres- entation.3 The US Food and Drug Administration (FDA) has approved HBOT as a safe adjunctive treatment to stimulate wound healing in patients with diabetes and it is known to accelerate the healing process in ischemic wounds and severe sepsis. Actually, there are 15 indica- tions for HBOTapproved by the Undersea and Hyperbaric Medicine Society, that can be divided in three groups:4 i) emergency medicine: air or gas embolism, Carbon Mon- oxide (CO) poisoning, Decompression Illness (DCI); ii) wound healing acceleration: acute thermal burn injury, compromised grafts and flaps, crush injury, compartment syndrome and other acute traumatic ischemia, delayed ra- diation injury (soft tissue and bone necrosis) enhancement of healing in selected problem wounds, idiopathic sudden sensorineural hearing loss, severe anemia; iii) exerting an- timicrobial effects: clostridial myositis and myonecrosis, intracranial abscess, necrotizing soft tissue infections, re- fractory osteomyelitis. The present narrative review aims to detail mechanisms of actions underlying HBOT, particularly oxy-inflammation, in some pathologies of these three groups. Abstract Hyperbaric Oxygen Therapy (HBOT) is a non-invasive method of O2 delivery that induces systemic hyperoxia. Hyperbaric chamber consists of a pressure vessel and a compressed breathing gas supply, which can regulate internal pressure. The chamber delivers 100% O2 to patients according to predetermined protocols and is monitored by trained personnel. HBOT relies on increasing the inspired O2 fraction (fiO2) and elevating the partial pressure of O2 (pO2). O2 is typically administered at pressures between 1.5 and 3.0 ATA for 60 to 120 minutes, depending on the clinical presentation. Currently, there are 15 indications for HBOT approved by the Undersea and Hyperbaric Medicine Society, categorized into three groups: emergency medicine, wound healing acceleration, and antimicrobial effects. The present narrative review aims to elucidate the mechanismsaction underlying HBOT, particularlyoxy-inflammation, in various pathologies within these categories. Key Words: oxygen, oxidative stress, inflammation, decompression-illness, reperfusion-injury, reoxygenation, infection, biomarkers. Eur J Transl Myol 35 (1) 12783, 2025 doi: 10.4081/ejtm.2025.12783 Oxy-inflammation in hyperbaric oxygen therapy applications Gerardo Bosco,1 Andrea Brizzolari,1 Matteo Paganini,1 Enrico Camporesi,2 Alessandra Vezzoli,3 Simona Mrakic-Sposta3 1Department of Biomedical Sciences, University of Padua, Padua, Italy; 2TEAM Health Anaesthesia, Tampa General Hospital, Tampa, Florida, USA; 3Institute of Clinical Physiology, National Research Council (IFC-CNR), Milan, Italy. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. - 52 - Oxy-inflammation in hyperbaric oxygen therapy applications Eur J Transl Myol 35 (1) 12783, 2025 doi: 10.4081/ejtm.2025.12783 Hyperbaric oxygen therapy related mechanisms Breathing O2 at hyperbaric pressure increases not only its partial pressure in tissues but also causes the Release Of- reactive Oxygen (ROS) and Nitrogen (RNS) species, sig- naling molecules involved in several physiological mechanisms phagocytosis of pathogens, modulatingactiv- ities and a regulatory ability in signal transductionprocesses during transduction of intercellularinformation (Figure 1).5 However, an excessive ROS/RNS production may cause ir- reversible damage to cells resulting in cell death by the ne- crotic and apoptotic pathways. Increased expression of inducible Nitric Oxide (NO) Synthase (iNOS) has been noted after HBO2 exposure on rats, potentially leading to further RNS generation and macroscopically to deteriora- tion of respiratory mechanics; hyperbaric exposure instead increased NOS expression without affecting respiratory properties.6 To avoid ROS/RNS damage, human body ac- tivates endogenous antioxidant defenses: as observed by Bosco et al., HBOTat 1.5-2.5 ATA plays a protective role against oxidative stress.7 Furthermore, thiols such as gluta- thione raise as consequence of HBO2 exposure, probably for their role in antioxidant response to protect cell compo- nents and preserve cellular homeostasis.7 ROS can regulate transcription factors including nuclear factor kappa B (NF- κB), activator protein-1 (AP-1), and hypoxia-inducible fac- tor (HIF-1α). These transcription factors influence the expression of several genes that express signaling mole- cules such as interleukins (IL-1β, IL-6), tumor necrosis fac- tor-α (TNF-α), and chemokines including IL-8.8 During inflammation, cytokines bound their related receptors in- ducing ROS generation, kinases and transcription factor ac- tivation. Cytokine and chemokine release activates recruitment of immune system cells such as neutrophils, monocytes, lymphocytes (natural killer cells [NK cells], T cells, and B cells), and mast cells. HBOT may inhibit pro- inflammatory interleukins includingIL-1β, IL-6 and IL-89 while seems to stimulate the release of anti-inflammatory IL-1α.10 Furthermore, another HBOT effect is represented by decreasing levels of high-sensitivity C-reactive protein (hs-CRP)11 and of the pro-inflammatory cytokines inter- feron-γ (IFN-γ), NF-κB and TNF-α.11 Experimental studies on small animals assessed that HBO2treatment lowers HIF- 1α levels. HBOT also suppresses Blood-Brain Barrier (BBB) permeability (as attested by the upregulation of BBB integrity markers zonula occludens-1 and claudin-5),12 en- dothelial extravasation and cerebral edema subsequent to the trauma.13 It decreases gene expression of inflammatory response cascade such as IL-8, caspase 3 and TNFα while higher levels of the anti-inflammatory IL-10 levels confirm the direct neuroprotective effect of HBOT.12 HBOT exhibits bactericidal properties against anaerobic microorganisms that are sensible to high concentration of ROS at high pO2. 2 These properties may be due to an increase of respiratory burst activity of neutrophil-like cells and the bacterial phagocytosis.14 On one hand antimicrobial activity slows down wound healing promoting a pro-inflammatory envi- ronment, on the other hand enhanced apoptosis resolves in- flammation favoring wound healing.14 HBOT promotes neovascularization through the combina- tion of two different process: the stimulation of new blood vessel growth from local endothelial cells (angiogenesis) combined with the differentiation in the bed of the wound of circulating stem/progenitor cells to generate new vessels (vasculogenesis).2 In bone marrow, HBOT stimulates NO Synthase (NOS) activity to produce NO, playing a crucial role in the mobilization of stem cells and promoting neo- vascularization. Another important neovascularization mechanism involves the role of HBOT related oxidative stress that induces Vascular Endothelial Growth Factor - 53 - Figure 1. Sketch of hyperbaric chamber and the effect of hyperbaric treatment. The O2 effect results in an increased supply of reactive oxygen species (ROS) and reactive nitrite species (RNS), with a consequent change in expression of transcription factors, proteins, inflammation status and promotion of vascularization and enhanced immunomodulatory properties. Oxy-inflammation in hyperbaric oxygen therapy applications Eur J Transl Myol 35 (1) 12783, 2025 doi: 10.4081/ejtm.2025.12783 (VEGF) activation favorited by HIF-1α.15 Exposure of Bone Marrow Mesenchymal Stem Cells (BM-MSCs) to HBO2 favorites the proliferation of osteogenically differen- tiated cells regulated by Wnt3a/β-catenin signaling path- way.16 On the other hand, Human Adipose-Derived Stem Cells (hADSC) proliferation has been observed after HBO2 exposure in presence of the pro-inflammatory cytoki- neTNF-α. The effect of TNF-α on hMSCs proliferation seems to be related to its concentration, suggesting a key role of this cytokine during bone tissue repair. Furthermore, HBOTmay promote osteogenic differentiation increasing the osteoblasts, calcium deposition, alkaline phosphatase activity and bone nodule.17 As reported by Thom et al., HBO2 stimulates stem progen- itor cells (SPCs) through a NO related mechanism18 where NO synthase activates metalloproteinase-9 to cleave the Stem Cell Factor (SCF) from its membranelinkage, leading to a SCF-mediated SPCs mobilization.Precursor cells from Colony Forming Cell (CFC) express VEGF receptor-2 (VEGFR-2), located in endothelial progenitors suggestinga role of some cells, mobilized by HBO2, in the endothelial regeneration. Hyperbaric oxygen therapy applications Decompression illness (DCI) treatment Decompression Illness (DCI) is caused by intravascular or extravascular bubbles that are formed as consequence of a reduction in environmental pressure (decompression). The term DCI is used to describe two different mechanisms which result in overlapping sets of symptoms: Arterial Gas Embolism (AGE) and Decompression Sickness (DCS). AGE occurs when expanding gas stretches and breaks al- veolar capillaries, allowing alveolar gas to enter the arterial circulation. It can be caused by gas trapped as a result of airways obstruction or by presence of pulmonary blebs and bullae.19 AGE manifestations include loss of consciousness, confusion, focal neurological deficits, cardiac arrhythmias or ischemia. DCS starts with the formation and the increase in size of extravascular and intravascular bubbles when the sum of the partial gas tensions (O2, N2, CO2, He and water vapor) is greater than the local absolute pressure. In diving, this state is made possible by the increase in tissue inert gas partial pressure that occurs when the gas (usually N2, occa- sionally He) is breathed at hyperbaric pressure. DCS dia- gnosis is based on a wide range of clinical manifestations,20 that involve different parts of the human body, including musculoskeletal pain, skin rush, paresthesia, hypesthesia and, less common, motor weakness, ataxia, vertigo, hearing loss, dyspnea, pulmonary edema, shock and death. HBOT is the definitive treatment for DCI due to the effect of hy- perbaric pressure to reduce bubble size, improved tissue ox- ygenation and hyperoxia that induces inhibition of leucocyte adhesion to damaged endothelium. Furthermore, 100% O2 is amelioration of tissue hypoxia caused by bub- ble-induced ischemia, mechanical injuries and biochemical damages.21 In the case of DCS, the treatment entity is chosen depending on the manifestation severity, patient re- sponse to HBOT and residual symptoms after the initial re- compression until the complete resolution.22 The most com- mon recompression schedule is US Navy Treatment Table 6 (NTT6; here in Table1) in which patients are compressed to 2.82 bar (equivalent to 18 m sea water depth) while breathing 100% O2, a pressure with an acceptable low risk of cerebral O2-associated toxic effects22 showing a high de- gree of success in resolving symptoms.23 For subjects with AGE, administration of repetitive treatments is rec- ommended until there is no further stepwise improvement, typically after 1-2 sessions, but occasionally up to 5-10.23 As concerning DCS, in most cases a single treatment is enough to resolve the episode while for patients with resid- ual symptoms after initial recompression, additional ses- sions are required to obtain a clinical stability.24 Recently, an inflammatory mechanism has been proposed in DCI, in addition to the mechanical ones. In this contest, HBOT may play a key role in DCI symptoms resolution for its ant in- flammatory properties to inhibit pro-inflammatory cyto- kines including IL-1β, IL-6 and IL-8.25 Carbon monoxide poisoning Carbon monoxide (CO) poisoning occurs when enough CO is inhaled to develop symptoms that include headache, nau- sea, vomiting, lethargy, dizziness, slowed thinking, short- ness of breath, and chest pain.25 CO primarily binds with hemoglobin (Hb) to form carboxyhemoglobin (COHb) pre- venting the blood from carrying O2 and expelling CO2 as carbaminohemoglobin (CO2Hb). CO poisoning leads to neural cell death suggesting an energy due to reduced Ad- enosine Triphosphate (ATP) production and oxidative stress.26 CO acts as double face molecule for its role as sig- naling molecule that regulates several functions in cardio- vascular system. On the other hand, an overproduction of free radicals and high CO level seem to alter the signaling pathways of ROS and CO in neurons that also may contrib- ute to the development of neurological disorders.27 Further- more, CO poisoning increases platelet activation trough the reaction of NO with superoxide anion (O2 2-) to lead to pe- roxynitrite (ONOO-) formation. Activated platelets promote neutrophil adhesion to degranulate and release Myeloper- oxidase (MPO). MPO exacerbates the inflammatory effects by triggering further neutrophil activation, adhesion, and degranulation. HBOT increases COHb dissociation rate respect to normo- baric O2 ameliorating Central Nervous System (CNS) in- juries trough improvement in mitochondrial functions, inhibition of lipid peroxidation, reduction of leukocyte ad- hesion to damaged vasculature and reduction in brain in- flammation.28 Reperfusion-reoxygenation injury Ischemia/Reperfusion (I/R) injury of ischemic-hypoxic or- gans may cause damage in different pathologies including pancreatitis, sepsis, intestinal ulcer, soft tissue crush in- juries, myocardial ischemia, and stroke or after cardiopul- monary bypass surgery.29 Lung injuries occur during the reperfusion phase suggesting the release of several medi- ators including neutrophils that, activated by TNFα, me- diate lung injury trough capillary obstruction, adhesion to - 54 - Oxy-inflammation in hyperbaric oxygen therapy applications Eur J Transl Myol 35 (1) 12783, 2025 doi: 10.4081/ejtm.2025.12783 endothelial cells, ROS release and protease. As reported by Yang et al. in a mice model of intestinal ischemia-re- lated injury, HBOT administered during artery ligation led to significantly lower TNF-α and IL-1β release; neutrophil sequestration in mice lungs was as well significantly lower in the HBO2 treated group.30 TNFα reduction after HBOT is attributable to the improved tissue oxygenation while neutrophils activation is inhibited administrating HBO2 during either ischemia or reperfusion period and deregu- lating intercellular adhesion molecule-1.31 HBOT benefits include also high energy compound preservation, reduc- tion of ischemic-hypoxic related lipid peroxidation, and decrease of sequestration in reperfused tissues. In an in- domethacin-induced enteropathy model, a significant re- duction in TNF-α and IL-1β levels was obtained in HBO2 treated rats; the cause of improved inflammation however has still to be determined, since it is not clear if TNF-α and IL-1β inhibition plays a secondary role in reducing - 55 - Table 1. HBOT therapeutic indications for the treatment of the above-described pathologies. Disease HBOT therapeutic N° of HBO2 sessions HBOT guidelines indication Decompression Illness Table 5 (US Navy) at 1-2 (Occasionally 5-10) U.S. Navy Manual and (Arterial Gas embolism 1.9-2.8 ATA Hyperbaric Oxygen Therapy and Decompression Table 6 (Us Navy) at Indications, 14th Edition Sickness) 2.82 ATA Table 7 (U.S. Navy) at 1.12-2.8 ATA Carbon Monoxide Mild intoxication: 1-3 (first session within Hyperbaric Oxygen Therapy Poisoning 2.5 ATA for 90 min 24 h) Indications, 14th Edition without air break Additional treatments are Severe intoxication: related to cognition 2.5-2.8 ATA for 113 min alterations without air break Ischemia/Reperfusion Undersea and Hyperbaric (I/R) injury*: Medical Society (UHMS) • Grafts and flaps 2.0-2.5 ATA for 90-120 min 1-2 treatment per day • Acute traumatic ischemia 2-2.4 ATA for 90-120 min 1-3 treatment per day (first session within 24 h) Skin and Soft tissue infections (SSTIs)*: • intracranial abscess 2.0-2.8 ATA for 60-90 min 2-3 treatment per day. Hyperbaric Oxygen Therapy (ICA) Indications, 14th Edition • Diabetic foot ulcer 2.0-2.5 ATA for 90-120 min Up to 30-40 treatment. (Wagner grade ≥3) • Necrotizing soft tissue 3 ATA for 90 min t.i.d. day 1-2 1-3 treatment per day infection (NSTI), (day1-2) type I 3 ATA for 90 min b.i.d. day 2-3 1-2 treatment per day (day 3-4) 3 ATA for 90 min once daily 1 treatment per day until stable until stable (Up to 30 sessions) Osteonecrosis 2.2 ATA for 112 min Up to 40 sessions Hyperbaric Oxygen Therapy Indications, 15th Edition Sensorineural Hearing 2.0-2.5 ATA for 90 min 1 treatment per day Hyperbaric Oxygen Therapy Loss (SNHL) (up to 10-20 sessions) Indications, 14th Edition *The optimal number of HBOT session is unknown, strongly related to patient reactivity. Oxy-inflammation in hyperbaric oxygen therapy applications Eur J Transl Myol 35 (1) 12783, 2025 doi: 10.4081/ejtm.2025.12783 inflammation.32 HBOT shows also immunosuppressive properties blocking erythrocyte-specific B and helper T cell release and inhibiting immunoglobulin production of NZB and MRL/lpr spleen cells. As demonstrated in a rat model of tourniquet-induced I/R skeletal muscle injury, those receiving HBO2 in the last hour of ischemia had lower levels of lactate and glycerol, without any effect on glucose levels.33 Glycerol is the final product of phospholipid degradation and has been supposed to be a biomarker of ischemic damage. HBOT reduces I/R glycerol concentration but it remains controversial if the glycerol rise is related to the glycolytic pathway or cell membrane damage.33 Lactate release during ischemia, associated with K increase, may contribute to organ damage. Repeated HBO2 sessions can stimulate aerobic metabolism increasing ATP production and reducing circulating lactate level. Glu- tamate is a contributing factor to the development of brain I/R injury that enhances ROS generation such as hydroxyl radical (•OH).34 HBO2has been studied also in models of brain I/R injury. For example, HBOT inhibits dopamine release avoiding its reaction with O2 and •OH to block the formation of the do- paminergic neurotoxin 6-hydroxydopamine. In a rat model of I/R brain injury, after a 30 minutes long occlusion of the middle cerebral artery, glutamate and hydroxyl radicals in the striatum peaked remained elevated during the reperfu- sion period in non-treated animals, whilst this rise was sig- nificantly attenuated in HBO2-treated rats; HBO2 seems therefore to reduce glutamate release and •OH generation contributing to protect nervous tissue.35 Low ATP produc- tion and Na+K+ATPase activity during ischemia can be ameliorated by HBOT to supply enough O2 to brain tissue, improving energy metabolism therefore reducing glutamate accumulation. The capacity of HBO2 to reduce •OH forma- tion may be related to inhibition of dopamine accumulation, believed to play a key role in ROS generation. Antioxidant enzymes, such as Catalase (CAT) and Super- oxide Dismutase (SOD), activity is essential in I/R injury prevention as observed investigating their scavenging abil- ity in I/R injured muscle. HBOT-related SOD and CAT ac- tivity in muscle I/Ris controversial, probably depending on fiO2 and muscle type. While Gregorevic et al. observed a reduction of CAT activity and an increase of that of SOD,36 Bosco et al. found an increase of CAT activity that seems to reflect the activation of antioxidant defenses against ROS/RNS.33 Furthermore, HBO2 is able to prevent lipid peroxidation following by decrease of CAT and SOD. After I/R, HBO2 exposure reduces CAT expression as con- sequence of decreased membrane lipid peroxidation, ev- idenced by decreased malondialdehyde (MDA) concentration.33 Skin and soft tissue infections Soft Tissue Infections (SSTIs) involve skin, subcutaneous fat, fascial layers, and musculotendinous structures37 with manifestations that can range from mild to severe. Mild in- fections are localized at the level of the skin and the under- lying tissues and include cellulitis, erysipelas, impetigo, ecthyma, folliculitis, furuncles, carbuncles and trauma-re- lated infections. Severe SSTIs involve deep tissues and in- clude deep abscesses, diabetes foot and decubitus ulcers, Necrotizing Fasciitis (NSTI), Fournier gangrene. SSTIs are typically caused by Staphylococcus aureus and Streptococ- cus pyogenes while S. aureus, Pseudomonas aeruginosa and Escherichia coli are the predominant pathogens iso- lated from hospitalized patients with SSTIs.38 A severe type of deep abscesses is the Intracranial Abscess (ICA), derived by infections such as sinusitis, otitis, mas- toiditis, or dental infection, hematogenous seeding and cra- nial trauma.39 In addition to surgery and antibiotic treatment, HBOT may confer several benefits (Figure 2). High fiO2 value can inhibit the growth of anaerobic pathogens and the neutrophil-mediated phagocytosis of in- fecting organisms.39 Furthermore, HBOT seems to promote the metabolic environment of acidosis and low oxidation- reduction potential enhancing the activity against pathogen organism and favoring the O2-dependent active transport of some antibiotic trough the bacterial wall. Diabetic foot ulcer is a lesion of skin and deeper tissues of the foot that leads to sore formation, representing the major complication of diabetes mellitus that prevents a regular transport of glucose into cells to avoid hyperglycemia. Hy- perglycemia leads to an excess of ROS generation, espe- cially O2 2-, that inhibits NO production, resulting in vasoconstriction and hypoxia. Furthermore, hyperglycemia induces thickening of capillary membranes, reducing O2 diffusion to surrounding tissue, decreasing endothelial NO Synthase (eNOS) activity and HIF-1 release. Diabetic chronic wounds promote the infiltration/accumulation of immune and pro-inflammatory cells such as polymorpho- nuclear neutrophils and macrophages. Macrophage become hyperpolarized exhibiting an altered clearance associated to the he dysregulation of the cell membrane protein Selec- tin P Ligand (SELPLG), resulting in the release of pro-in- flammatory molecules. The hyperglycemia induces an upregulation of α-defensin proteins promoting IL-8 expres- sion and enhancing the recruitment of immune system cells followed by the release of other pro-inflammatory cyto- kines and chemokines. HBOT delivers O2 in injured tissues40 promoting neovas- cularization and collagen deposition at the site of hypoxic tissues reversing hypoxia caused by diabetes mellitus and stimulating several growth factors including VEGF, basic Fibroblast Growth Factor (FGF), Transforming Growth Factor beta-1 (TGF-β), NO, and Platelet Derived Growth Factor (PDGF).41 Furthermore, HBOT induces the mo- bilization of endothelial SPCs through eNOS increasing NO availability.41 HBOT reduces expression of inflammatory cytokines including IL-1 and IL-2, increasing angiogenesis, reducing the metalloproteinase expression, and promoting both antibiotic and leucocyte function against pathogens.5 The worst type of SSTIs is represented by NSTI, also known as necrotizing fasciitis, a bacterial fast-progressing and life-threatening disease characterized by widespread necrosis in the soft-tissue compartment. NSTI is often ac- companied by systemic toxicity due to severe inflammatory response syndrome which may progress to hemodynamic instability, septic shock, multiple organ failure, and death. NSTI may evolve in a clinical picture in which an intense inflammatory response leads to an excessive platelets acti- - 56 - Oxy-inflammation in hyperbaric oxygen therapy applications Eur J Transl Myol 35 (1) 12783, 2025 doi: 10.4081/ejtm.2025.12783 vation resulting in endothelial damage, vascular occlusion, and widespread necrosis in the deep tissues. During infections, activation of neutrophils and inflam- matory molecules, induced by shock-related I/R leads to in increased production of free radicals, resulting in increased oxidative stress. HBOT is an auxiliary intervention to stan- dard care in NSTI due to its antimicrobial properties, mod- ulating oxidative stress trough the release of ROS and RNS42 that seem to be effective against various pathogens. In NSTI patients, HBO2 diminishes the presence of tissue edema and hypoxia at infection site, promoting ROS gen- eration that can react with bacterial DNA and macromole- cules resulting in lethal cell effects. Some authors found an increase of MPO and SOD after HBOT session in subjects with NSTI suggesting an immunomodulatory action of HBO2 by oxidative stress induction and consequent antiox- idant defense reaction.43 Oxidative stress seems to play a crucial role for MPO release from immune cells and O2 2- as MPO substrate to promote pathogen elimination by neutro- phils. Furthermore, heme oxygenase-1 (HO-1) activity is fundamental against bacterial infection and HBO2 treatment increases HO-1 expression stimulating endogenous anti-in- flammatory cytokines and antioxidant defenses.44 Similarly, to oxidative stress markers,43 high levels of in- flammatory markers are associated with disease severity and mortality. In severe septic shock patients, IL�1β, IL�6 and Granulocyte Colony-Stimulating Factor (G-CSF) have been proposed as indicators to predict early mortality, while IL-6 and G-CSF are indicated as potential predictors of organ dysfunction deterioration, suggesting a pivotal role of IL-1β, IL-6, and IL-10 in sepsis onset. Some authors ob- served that IL-1β, IL-6, IL-10, and IL-18 seem to play a key role in NSTI pathophysiology,45 suggesting an exces- sive pro inflammatory response during severe infection trig- gered by toxin production and cytokines cascade activation. In presence of septic shock, this intense cytokine release can damage the endothelium, leading to a Systemic Inflam- matory Response Syndrome (SIRS) and resulting in a mul- tiple organ failure and elevated mortality.46 HBOT seems to have regulatory properties on the IL-1β expression dur- ing infectionand to stimulate immune-modulatory activities including IL-10 modulation in animal model, depending on timing and dosage.47 In patients with Group A-Streptococ- cusNSTI, HBOT may induce immunomodulatory effects by reducing G-CSF and IL-6 levels. In the case of septic shock, it seems endothelial layer could play a crucial role - 57 - Figure 2. Hyperbaric Oxygen therapy (HBOT) is an adjuvant treatment in various conditions: ischemic/reperfusion, necrotizing soft tissue infection, compartment syndrome and orthopedic. Oxy-inflammation in hyperbaric oxygen therapy applications Eur J Transl Myol 35 (1) 12783, 2025 doi: 10.4081/ejtm.2025.12783 due to adhesion molecule expression on the endothelium and leukocyte that trigger a cascade reaction with the re- lease of immune cells to the endothelium layer. Among these molecules, soluble intercellular adhesion molecule-1 (sICAM-1), a known marker of endothelial activation, may be correlated to sepsis severity, organ function alterations and patient mortality.48 sICAM-1 may act trough a regu- latory mechanism to reduce inflammation giving protection from damage caused by excessive inflammation response. Release of sICAM-1 by Neutrophil Elastase (NE) and A disintegrin and metalloproteinase domain 17 (ADAM17) seems to reduce leukocyte adhesion to endothelium surface. This mechanism is combined with the sICAM-1activity as potential competitive antagonist to residual endothelial ICAM-1 by binding to its ligands on the leukocyte surface. HBO2 immunomodulatory effects increase sICAM-1 in NSTI patients with NSTI and septic shock respect to the non-septic shock patients,49 leading to an improved survival rate of subject with severe illness. Furthermore, O2 mod- ulates ADAM17 when ROS increase activity of NE and ADAM17 and this might be a possible usefulness of HBO2 treatment to improve survival in NSTI patients, exploiting its immunomodulatory effects. HBOT seems therefore to reduce the risk of amputation in patients with NSTI in pa- tients with limb localization and reduces the mortality in subjects with Fournier gangrene.50 Osteonecrosis Avascular necrosis (AV), known also as osteonecrosis, is a pathologic process that results from the death of bone tissue due to the interruption of blood supply.51 The most common type is the Avascular necrosis of the Femoral Head (AVFH), associated to ischemic process and other mechanism includ- ing oxidative stress, blood coagulation and cell death. Other sites at AV risk are femoral condyles, head of the humerus, and the proximal regions of the talus and scaphoid bone. These areas located farthest from the bone’s blood supply and are covered by cartilage, which limits their exposure to nearby blood vessels, making them susceptible to ischemic necrosis.52 AVFH may be a consequence of an altered bone remodeling, in which Osteoprotegerin (OPG), the Receptor Activator of NF-kB Ligand (RANKL), and the Receptor Activator of NF-kB (RANK) system play a key role. RANK, a transmembrane protein present on osteoclasts and their hematopoietic precursor cells (circulating monocytes), binds to RANKL stimulating osteoclast differentiation, ac- tivation and enhancing their adherence to bone surfaces. Then, RANK initiates intracellular signaling pathways by recruiting TNF receptor-associated factor 6 (TRAF6), lead- ing to NF-kB activation. OPG, released by osteoblasts, acts to reduce RANKL’s interaction with RANK, thereby inhib- iting osteoclast genesis and bone resorption.53 Any pertur- bation of OPG/RANKL/RANK system may lead to a pathological condition such as degradation and collapse of the femoral head. HBO2 has been proposed as adjunctive therapy bone dis- eases (Figure 2), including AVFH reducing pain symptoms.52-54 During AVFHat early stages, HBO2 pro- motes oxygenation of hypoxic tissues, reducing edema and inducing vasoconstriction. Furthermore, HBO2 improves ischemic bone cell oxygenation without the need for the energy required for O2 dissociation from circulating hemo- globin.52 As reported by Vezzani et al., HBOT upregulates circulating OPG early after initiation of treatment, thus sug- gesting a reduction in osteoclast activation and formation.54 Some authors observed mRNA expression of OPG, RANKL and RANK genes were comparable in healthy tis- sues while most necrotic tissue showed higher and/or very low OPG and RANKL protein levels compared to their re- spective mRNA, suggesting the existence of a post-trans- lational control especially in the ill tissues. HBO2 may enhance healing of necrotic wounds by stimu- lating angiogenesis, fibroblast proliferation, osteoblast pro- liferation, and collagen formation55 and these mechanisms are trigged by modulation of O2 sensitive transcription fac- tors as well as ROS-mediated signaling pathways them- selves.42 During the early treatments, HBO2 may enhance endogenous antioxidant defense activity and detoxify ca- pacity improving cell protection against free radical dam- age.2 Bosco et al. found that HBOT results in an anti-inflammatory action in patients with AVFH decreasing circulating TNF-α, IL-6, and ROS levels.55 TNF-a together with IL-1 and Il-6 cause a strong activation of osteoclasts and have multiple links with ROS generated through in- flammation in AVFH. Such reduction in bone-resorbing cy- tokines can therefore positively influence the RANK/RANKL pathway modulating osteoclast activation and differentiation andmitigate overall inflammation, lead- ing to beneficial resolution for the patient.54 Sensorineural hearing loss Sensorineural Hearing Loss (SNHL) is an impairment of the structure and/or function of human auditory apparatus characterized by injuries of cochlear Hair Cells (HCs), Spi- ral Ganglion Neurons (SGNs), auditory transmission path- ways and nervous tissue.56 Other SNHL-associated symptoms include tinnitus, aural fullness, dizziness and ver- tigo. Oxidative stress is a common cause of several types of SNHL, including age-related, genetic, and ototoxic drug- and noise-induced hearing loss.57 Indeed, cochlea is suscep- tible to an excessive ROS production, induced by external factors such as noise or ototoxic drugs, that overwhelm the antioxidant defenses of hair cells, resulting in a cochlear cell degeneration. The alteration of mitochondrial functions triggers the c-Jun N-Terminal Kinase/Mitogen-Activated Protein Kinase (JNK/MAPK) apoptotic pathway in hair cells against oxidative stress. Furthermore, SNHL may also have a thrombotic origin that leads to the obstruction of cochlea vessels. Under throm- botic conditions, oxidative stress can alter RBC function resulting in a hypercoagulable state and enhancing binding to vascular endothelial cells, improving the susceptibility to SNLH.58 Inaddition to cell damage, ROS circulation promotes in- flammation trough the production of pro inflammatory cy- tokines such as IL-1β, IL-6 and TNFα. An excessive noise stimulation increases Blood-Labyrinth Barrier (BLB) re- sulting in an elevated level of circulating white blood cells, neutrophils, and monocytes and exacerbating the infiltration of inflammatory factors into the cochlea. HBOT is used to - 58 - Oxy-inflammation in hyperbaric oxygen therapy applications Eur J Transl Myol 35 (1) 12783, 2025 doi: 10.4081/ejtm.2025.12783 treat patients with SNHL associated with steroid therapy or as salvage therapy. HBOT increase O2 supply to cochlea, reducing hypoxia, edema and improving body response to infection and ischemia, improving RBC, hematocrit and he- moglobin levels and antioxidant defenses trough the release of SOD.59 Conclusions Hyperbaric Oxygen Therapy (HBOT) is a significant med- ical intervention that leverages the increased partial pressure of O2 to treat various acute and chronic conditions. The ther- apy’s mechanisms of action, which include the modulation of ROS and RNS, provide both therapeutic benefits and pose potential risks if not properly managed. HBOT’s effi- cacy in treating conditions such as DCI, carbon monoxide poisoning, I/R injuries, and severe skin and soft tissue in- fections underscores its versatility and critical role in med- ical care. Its application ranges from enhancing wound healing and exerting antimicrobial effects to promoting neo- vascularization and modulating inflammatory responses. For DCI, HBOT reduces bubble size and improves tissue oxygenation, proving essential for divers and others experi- encing rapid decompression. In cases of carbon monoxide poisoning, HBOT accelerates the dissociation of car- boxyhemoglobin, reducing neural damage and inflamma- tion. For I/R injuries, the therapy mitigates tissue damage through improved oxygenation, reduced oxidative stress, and modulation of inflammatory cytokines. HBOT’s role in treating severe skin and soft tissue infections, particularly in diabetic foot ulcers and necrotizing fasciitis, highlights its antimicrobial properties and ability to enhance tissue re- pair and immune response. Despite, its broad applications and benefits, HBOT must be administered carefully, con- sidering the potential for oxidative stress and cell damage due to excessive reactive species generation. Proper proto- cols (Table 1) and trained personnel are essential to maxi- mize benefits and minimize risks. Future research should continue to refine HBOT protocols and expand its thera- peutic indications, potentially uncovering new mechanisms and applications that can further benefit patients across var- ious medical fields. Take messages Versatile treatment: HBOT is a versatile treatment modality effective in a wide range of medical conditions, including decompression illness, carbon monoxide poisoning, ische- mia/reperfusion injuries, and severe skin and soft tissue in- fections. Mechanisms of action: The therapy works by increasing the partial pressure of oxygen in tissues, enhancing reactive ox- ygen and nitrogen species production, which are crucial in pathogen phagocytosis and cellular signaling. Wound healing and antimicrobial effects: HBOT promotes wound healing and exerts antimicrobial effects by enhanc- ing oxygen delivery to tissues, reducing inflammation, and improving immune response. Inflammation modulation: The therapy modulates inflam- matory responses by inhibiting pro-inflammatory cytokines and promoting anti-inflammatory cytokines, crucial for conditions like necrotizing fasciitis and diabetic foot ulcers. Neovascularization: HBOT stimulates neovascularization, combining angiogenesis and vasculogenesis, which is vital for tissue repair and regeneration, particularly in hypoxic and ischemic conditions. Risks and management: While beneficial, HBOT poses risks related to oxidative stress. Proper administration pro- tocols and trained personnel are essential to ensure safety and efficacy, highlighting the need for ongoing research and protocol refinement. List of abbreviations ADAM17, A disintegrin and metalloproteinase domain 17 AGE, arterial gas embolism AP-1, activator protein-1 ATP, adenosine triphosphate AV, Avascular necrosis AVFH, avascular necrosis of the femoral head BBB, blood-brain barrier BLB, blood-labyrinth barrier BM-MSCs, bone marrow mesenchymal stem cells CNS, central nervous system DCI, decompression illness DCS, decompression sickness CAT, catalase CO, carbon monoxide COHb, carboxyhemoglobin CO2Hb, carbaminohemoglobin COPD, chronic obstructive pulmonary diseases eNOS, endothelial NO synthase FDA, Food and Drug Administration FGF, fibroblast growth factor fiO2, oxygen fraction G-CSF, granulocyte colony-stimulating factor HBOT, hyperbaric oxygen therapy HO-1, heme oxygenase-1 hADSC, human adipose-derived stem cells Hb, hemoglobin HIF-1α, hypoxia-inducible factor hs-CRP, high-sensitivity C-reactive protein ICA, intracranial abscess IFN-γ, interferon-γ IL, interleukin I/R, ischemia/reperfusion iNOS, inducible nitric oxide synthase JNK/MAPK, c-Jun N-terminal kinase/mitogen-activated protein kinase MDA, malondialdehyde MPO, myeloperoxidase NE, neutrophil elastase NF-κB, nuclear factor kappa B NK cells, natural killer cells NO, nitric oxide NSTI, necrotizing fasciitis NTT6, US Navy treatment Table 6 (NTT6) O2 2-, superoxide anion •OH, hydroxyl radical ONOO-, peroxinitrite - 59 - Oxy-inflammation in hyperbaric oxygen therapy applications Eur J Transl Myol 35 (1) 12783, 2025 doi: 10.4081/ejtm.2025.12783 OPG, osteoprotegerin OSAS, obstructive sleep apnea syndrome PDGF, platelet derived growth factor pO2, partial oxygen pressure RANK, NF-kB receptor RANKL, NF-kB Ligand RNS, reactive nitrogen species ROS, reactive oxygen species SCFs, stem cell factor SELPLG, cell membrane protein selectin P ligand sICAM-1, soluble intercellular adhesion molecule-1 SIRS, systemic inflammatory response syndrome SNHL, sensorineural hearing loss SOD, superoxide dismutase SPCs, stem progenitor cells SSTIs, Soft tissue infections TGF-β, transforming growth factor beta-1 TNF-α, tumor necrosis factor-α TRAF6, TNF receptor-associated factor 6 VEGF, vascular endothelial growth factor Contributions Conceptualization, AV, SM-S and GB; methodology, AV, SM-S and GB; writing—original draft preparation, AV and AB; writing—review and editing, SM-S, MP, EC and GB; visualization, AB, SM-S, MP, EC and GB; supervision, SM-S and GB. All authors have read and agreed to the pub- lished version of the manuscript. Conflicts of interest The authors declare no conflicts of interest. Funding This work was primarily supported by the Office of Naval Resource (ONR) Undersea Medicine Program (N00014- 23-1-2757). Institutional review board statement Not applicable. Informed consent statement Not applicable. Data availability statement Not applicable. Corresponding author Simona Mrakic-Sposta Institute of Clinical Physiology, National Research Council (CNR), Milan, Italy. ORCID ID: 0000-0001-7359-2690 E-mail: simona.mrakicsposta@cnr.it Co authors Gerardo Bosco ORCID ID: 0000-0001-6595-7944 E-mail: gerardo.bosco@unipd.it Andrea Brizzolari ORCID ID: 0009-0006-4935-6587 E-mail: andrea.brizzolari@unipd.it Matteo Paganini ORCID ID: 000-0002-7556-6928 E-mail: matteo.paganini@unipd.it Enrico Camporesi ORCID ID: 0000-0003-3548-1097 E-mail: ecampore@usf.edu Alessandra Vezzoli ORCID ID: 0000-0002-0277-163X E-mail: alessandra.vezzoli@cnr.it References 1. Martin DS, Grocott III MP. Oxygen therapy in anaes- thesia: the yin and yang of O2. Br J Anaesth 2013: 111:867-71. 2. Camporesi EM, Bosco G. Mechanisms of action of hy- perbaric oxygen therapy. Undersea Hyperb Med 2014:41:247-52. 3. Bennett M, Best TM, Babul S, et al. Hyperbaric oxygen therapy for delayed onset muscle soreness and closed soft tissue injury. Cochrane Database Syst Rev 2005:2005:CD004713. 4. Ortega MA, Fraile-Martinez O, Garcia-Montero C, et al. 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Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Submitted: 4 July 2024. Accepted: 27 July 2024. Early access: 20 January 2025. - 62 -