Heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke

Li, Ru; Wei, Riqing; Liu, Chenxin; Zhang, Keying; He, Sixiao; Liu, Zhifeng; Huang, Junhao; Tang, Youyong; An, Qiyuan; Lin, Ligen; Gan, Lishe; Zhao, Liying; Zou, Xiaoming; Wang, Fudi; Ping, Yuan; Ma, Qiang

doi:10.1016/j.apsb.2024.05.007

Cited by 5 publications

(4 citation statements)

References 58 publications

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“…Aligning with findings reported in a murine model of hindlimb ischemia, where increased HO-1 expression promoted activation of the NLRP3 inflammasome ( 46 ), Li et al. recently demonstrated that a heat shock-induced up-regulation in HO-1 triggered macrophage ferroptosis and IL-1β-mediated inflammation ( 47 ). With high HO-1 expression linked to vascular and cellular injury, as well as exacerbated inflammatory responses ( 46 , 47 ), could the increased HO-1 expression that has been detected in skin samples of burns patients negatively impact upon the process of wound healing ( 22 )?…”

Section: Discussionsupporting

confidence: 66%

“…Interestingly, changes in ferroptosis-related genes (FRGs) were recently identified in leukocytes isolated from thermally-injured patients, with these changes associated with survival ( 49 ). Given that we detected increased HO-1 expression in PBMCs of trauma patients, and HO-1 is implicated in ferroptosis ( 47 ), future studies should investigate whether the expression of FRGs are also altered post-trauma and, if so, how this impacts upon clinical outcomes. Based on existing literature, it is currently unclear as to what the potential immunological consequences of a trauma-induced increase in HO-1 expression would be.…”

Section: Discussionmentioning

confidence: 93%

“…recently demonstrated that a heat shock-induced up-regulation in HO-1 triggered macrophage ferroptosis and IL-1β-mediated inflammation ( 47 ). With high HO-1 expression linked to vascular and cellular injury, as well as exacerbated inflammatory responses ( 46 , 47 ), could the increased HO-1 expression that has been detected in skin samples of burns patients negatively impact upon the process of wound healing ( 22 )? This question is worthy of investigation given that administration of ferroptosis inhibitors has been reported, across multiple rodent models, to accelerate wound repair ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

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Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression

Tullie,

Nicholson,

Bishop

et al. 2024

Front. Immunol.

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BackgroundTraumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of total heme in over 200 traumatic and thermally-injured patients in order to examine its relationship with clinical outcomes and post-injury immune suppression.MethodsBlood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4–72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following in vitro heme treatment was also examined.ResultsBurns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4–12 and 48–72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with ex vivo LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response.ConclusionsMajor injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression

Tullie,

Nicholson,

Bishop

et al. 2024

Front. Immunol.

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“…The pathogenesis of HS involves a transition from a compensable thermoregulatory state to a non-compensable one. Thermoregulatory failure exacerbates the pathophysiological processes involved—including severe inflammation, multiple organ injury, and disseminated intravascular coagulation—which result from the combination of extreme hyperthermia and circulatory collapse ( Epstein and Yanovich, 2019 ; Li R et al, 2024 ). Prompt recognition and effective on-site cooling can rapidly reverse the organ dysfunction caused by HS, in most cases.…”

Section: Discussionmentioning

confidence: 99%

Heat acclimation with probiotics-based ORS supplementation alleviates heat stroke-induced multiple organ dysfunction via improving intestinal thermotolerance and modulating gut microbiota in rats

Li,

Chen,

Wang

et al. 2024

Front. Microbiol.

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Heat stroke (HS) is a critical condition with extremely high mortality. Heat acclimation (HA) is widely recognized as the best measure to prevent and protect against HS. Preventive administration of oral rehydration salts III (ORSIII) and probiotics have been reported to sustain intestinal function in cases of HS. This study established a rat model of HA that was treated with probiotics-based ORS (ORSP) during consecutive 21-day HA training. The results showed that HA with ORSP could attenuate HS-induced hyperthermia by regulating thermoregulatory response. We also found that HA with ORSP could significantly alleviate HS-induced multiple organ injuries. The expression levels of a series of heat-shock proteins (HSPs), including HSP90, HSP70, HSP60, and HSP40, were significantly up-regulated from the HA training. The increases in intestinal fatty acid binding protein (I-FABP) and D-Lactate typically seen during HS were decreased through HA. The representative TJ proteins including ZO-1, E-cadherin, and JAM-1 were found to be significantly down-regulated by HS, but sustained following HA. The ultrastructure of TJ was examined by TEM, which confirmed its protective effect on the intestinal barrier protection following HA. We also demonstrated that HA raised the intestinal levels of beneficial bacteria Lactobacillus and lowered those of the harmful bacteria Streptococcus through 16S rRNA gene sequencing. These findings suggest that HA with ORSP was proven to improve intestinal thermotolerance and the levels of protective gut microbiota against HS.

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Heat Stroke and Hyperosmolar Hyperglycemia State: Two Faces of the Same Coin (Dehydration) in the Hajj Journey - How to Reduce Deaths Among Pilgrims

Ahmed,

Akl,

elkazzaz

2024

Preprint

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Heat stroke (HS) and hyperosmolar hyperglycemic state (HHS) are critical conditions frequently affecting pilgrims during the Hajj, especially with temperatures exceeding 50°C (122°F). This brief commentary examines the interconnected risks of HS and HHS among Hajj pilgrims, focusing on the heightened vulnerability of those with diabetes. We discuss the mechanisms linking dehydration, hyperthermia, and hyperglycemia, emphasizing the need for early recognition and intervention. Preventive strategies such as heat acclimation, proper hydration, and probiotic-based oral rehydration solutions (ORSP) are highlighted. Additionally, the use of smart ID medical bracelets for diabetic patients can improve emergency response. Implementing these measures can reduce the incidence and severity of heat stroke and hyperosmolar hyperglycemic state, protecting the health of pilgrims.

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Heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke

Cited by 5 publications

References 58 publications

Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression

Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression

Heat acclimation with probiotics-based ORS supplementation alleviates heat stroke-induced multiple organ dysfunction via improving intestinal thermotolerance and modulating gut microbiota in rats

Heat Stroke and Hyperosmolar Hyperglycemia State: Two Faces of the Same Coin (Dehydration) in the Hajj Journey - How to Reduce Deaths Among Pilgrims

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