Intestinal I/R injury is common in the clinic. Many pathological processes are associated with intestinal I/R injury, such as volvulus, intussusception, incarcerated hernia, acute intestinal ischemia, shock, trauma; certain surgical procedures, such as bowel resection and transplantation, are also associated (Acosta, 2010; Stone and Wilkins, 2015). Intestinal I/R is a common pathophysiological process in many diseases and is closely related to the structural characteristics of the intestine. First, the small intestine is supplied mainly by the superior mesenteric artery, and the nerve endings of the small intestine communicate directly with the arterioles and veins. Second, in various emergencies, the body prioritizes the supply of blood to vital organs such as the heart and brain, and the supply of blood to the gastrointestinal tract is correspondingly reduced, which contributes to the occurrence of intestinal ischemia, increases intestinal permeability, and weakens intestinal barrier function (Liu et al., 2016). Intestinal mucosal barrier dysfunction and increased permeability enable numerous bacteria or toxins to enter the blood or lymphatic channels in the circulatory system, leading to SIRS. When treatment is inappropriate or not timely, the condition eventually develops into MODS (Wu et al., 2017). Extensive intestinal epithelial cell death is a major cause of intestinal mucosal barrier dysfunction, and further development leads to systemic inflammation and distal organ dysfunction (Cheng J. et al., 2013). Microcirculation disturbance and organ injury after intestinal I/R are complicated pathological processes that mainly involve metabolic injury and oxidative stress during ischemia and reperfusion. During ischemia, vascular closure or obstruction leads to a lack of oxygen and nutrients in cells, impairing the expression of mitochondrial respiratory chain ATP synthase (Lin et al., 2013; Tu et al., 2013; Li et al., 2014a; He et al., 2014) and resulting in a decrease in ATP synthesis coupled with continued depletion of ATP, leading to ATP deficiency (Kalogeris et al., 2012). Microcirculatory dysfunction induced by I/R injury may lead to multiple organ damage (Eltzschig and Eckle, 2011), organ fibrosis (Rai et al., 2017), and even organ failure (Katseni et al., 2015), whose prevention and treatment are critically important.

Inflammation plays an important role in I/R. Neutrophils and white blood cells are recruited to produce cytokines, chemokines, and inflammatory mediators, which induce inflammatory responses (Kvietys and Granger, 2012; Frangogiannis, 2015). During reperfusion, the immune cells delivered by the blood reenter the tissue, and leukocyte sequestration increases significantly. To save ischemic tissue, cell metabolism should be accelerated, but during reperfusion, the influx of oxygen into the blood promotes the production of ROS by xanthine oxidase (XO) and NADPH oxidase. Necrotic cells in ischemic tissue emit danger signals, and adhesion mediators are formed between innate immune cells and postcapillary veins. Finally, neutrophils are isolated into ischemic tissue. Neutrophils activate NADPH oxidase-dependent respiratory bursts, release hydrolases, produce highly toxic hypochlorite and N-chloramine through MPO enzyme activity, and secrete pore-forming molecules, causing extensive collateral damage to blood vessels and parenchymal cells. Infiltrating neutrophils induce reperfusion damage that amplifies ischemia-induced cell damage (Ford, 2010; Kvietys and Granger, 2012; Frangogiannis, 2015).

Studies have shown that SIRS can directly cause MODS. SIRS refers to stimulation, by severe infectious or noninfectious factors, of the activation of inflammatory cells. This stimulation producing many inflammatory mediators, to which the body has a systemic inflammatory cascade response. MODS, caused by an uncontrolled inflammatory response, is related not only to the overexpression and secretion of inflammatory mediators but also to the abnormal production of host anti-inflammatory mediators of endogenous inhibitors. The body produces endogenous anti-inflammatory responses that decrease immune function and increase susceptibility when the body is injured or infected. In 1996, Bone RC introduced the concept of compensatory anti-inflammatory response syndrome (CARS) (Bone, 1996). Physiologically, proinflammatory and anti-inflammatory processes exist in a balanced state; when proinflammatory processes become dominant, the external response and cell damage are induced, which manifest as SIRS. In contrast, when anti-inflammatory processes predominate, the host-to-external stimulus response is low, which increases susceptibility to infection and performance similar to CARS. When both are hyperactive, the immune system exhibits are more serious disorder known as mixed anti-inflammatory response syndrome (MARS). Either CARS or MARS reflects disorder of the body’s inflammatory response and destruction of the internal environment, laying the foundation for MODS. Infection-related or non-infection-related factors can activate inflammatory cells to release a variety of cytokines and inflammatory mediators, such as IL-1, IL-6, IL-8, IL-12, TNF-α, NO, leukotriene B4, IFNα, and IFNβ (McNab et al., 2015; Chen et al., 2017) to participate in the body’s inflammatory immune response in order to resist external pathogenic factors. Anti-inflammatory cytokines such as IL-4, IL-5, and IL-13 also increase significantly to prevent excessive inflammatory injury (Wojdasiewicz et al., 2014; Kalogeris et al., 2016; Boshtam et al., 2017). When inflammatory and anti-inflammatory responses are out of balance, multiple inflammatory mediators form a cascade effect. The interactions of these mediators induce a variety of pathophysiological processes, including the endothelial cell inflammatory response, increased vascular permeability, inflammatory infiltration, and tissue damage. This eventually leads to the occurrence of MODS.

In the physiological state, the intestinal mucosal barrier acts as a filter for the gut, enabling the absorption of nutrients and preventing bacteria, macromolecules, and toxic compounds from entering the internal environment (Camilleri et al., 2012). Intestinal epithelial cells, microbes, and the immune system work together to maintain intestinal homeostasis. Impairment of intestinal integrity is an important cause of SIRS and MODS. Breakdown of the intestinal barrier can lead to local intestinal dysfunction and absorption of toxic substances into the blood, resulting in bacterial translocation and systemic abnormalities such as sepsis (Assimakopoulos et al., 2018). These changes lead to increased intestinal permeability. Bacteria, antigens, and toxic substances activate mucosal membrane immune responses through the intestinal mucosa, leading to abdominal pain and diarrhea (Farhadi et al., 2007). These inflammatory mediators signal to epithelial cells, nerve cells, and muscle cells, leading to intestinal dysfunction (Macdonald and Monteleone, 2005). Increased intestinal permeability under conditions of severe trauma, shock, and critical conditions and barrier damage maintain an inflammatory environment, leading to changes in microbial toxicity and acute gastrointestinal injury (Piton et al., 2011). As intestinal permeability increases, proinflammatory cytokines such as TNF-α, IL-1, and IL-6 are released into the systemic circulation, fluid seeps out of the intestine, and angioedema occurs (Angus and van der Poll, 2013). Proinflammatory cytokines also induce changes in intestinal tight connection proteins, further increasing intestinal permeability (Shea-Donohue et al., 2010; Zhou et al., 2015). In addition, the toxicity and invasiveness of the gut microbiome increases, and translocating bacteria, cytokines, and endotoxins are released from the intestine. These factors cause damage to distant organs, so the intestine is considered to be the origin of sepsis and MODS (Deitch, 2010).

A series of pathophysiological changes and abnormal cell metabolism occur in intestinal tissue due to ischemia and hypoxia. On the one hand, microcirculation disorder manifests as microcirculation congestion, and blood flow stasis causes tissue hypoxia to produce metabolic acidosis, induces intravascular coagulation, and forms microthrombi. Microthrombi aggravate hypoxia and metabolic acidosis of tissues and organs, forming a vicious cycle. Severe hypoxia and acidosis can damage vascular endothelial cells, increase vascular permeability, and cause widespread edema in tissue. In addition, the stability of lysosomes is destroyed, the lysosomal membrane ruptures, and cells undergo self-soluble necrosis. These processes work together to cause systemic multiple organ dysfunction. On the other hand, histiocyte metabolism is affected. Metabolic disorders occur due to hypoperfusion and hypoxia of the gut. The body is in a state of stress; therefore, catecholamine and adrenal corticosteroid release increases, metabolic decomposition is exacerbated, and energy consumption significantly increases. Under hypoxia, cell anaerobic metabolism increases, and lactic acid accumulates, leading to metabolic acidosis.

The human intestine is rich in mitochondria, which participate in numerous redox reactions and produce ATP by oxidative phosphorylation. Such energy metabolism is the main source of oxidants. Studies have shown that mitochondria are major participants in the process of intestinal oxidative stress. When the intestine is exposed to oxidative stress, it produces many reactive oxygen species (ROS) and reactive nitrogen species (RNS). This causes the body’s oxidant and antioxidant defenses to be out of balance, leading to aging and disease. ROS and RNS come from many different sources, including mitochondrial respiratory electron transport chains, xanthine oxidase, NADPH oxidase, and the NO synthetase system (Hu C. et al., 2019). In intestine cells, mitochondria are the main sources of ROS, mainly mitochondrial respiratory chain enzyme complex I and complex III (Rabbani and Thornalley, 2019). When the process of mitochondrial oxidative phosphorylation is disturbed, the formation of ATP is reduced significantly, and the propensity for ROS formation is increased (Toldo et al., 2018). In the physiological state, the body has many ways to regulate the oxidative stress produced by mitochondrial ROS, such as the superoxide dismutase system, which can convert reactive superoxide radicals into hydrogen peroxide and detoxify it further by enzyme catalysis. In the case of intestinal ischemia, the restoration of blood supply increases ROS, leading to mitochondrial dysfunction and intestinal mucosal cell damage. The inflammatory response eventually disrupts intestinal mucosal barrier function.

In addition, mitochondria can not only produce energy but also regulate calcium homeostasis. Na⁺-K⁺-ATPase and Ca²⁺-ATPase, which are essential for maintaining the normal structure and function of mitochondria, are located on the mitochondrial membrane. When the activity of the two ion pumps changes, mitochondrial membrane permeability transition pores can be activated, resulting in the functional and structural breakdown of mitochondria and causing cell death (Yue et al., 2012). Other studies have confirmed that when hypoxia occurs in the intestine, the activity of the mitochondrial respiratory chain enzyme complex decreases. This produces large numbers of ROS and significantly reduces ATP synthesis (Duchen, 2004). In addition, the atpase activity in intestinal mitochondria changes, Na⁺-K⁺-ATPase activity decreases, and Ca²⁺-ATPase activity increases (Baines, 2009). Changes in mitochondrial membrane potential cause dysfunction, lead to the release of large amounts of ROS and apoptosis-promoting factors, and eventually induce apoptosis or necrosis of intestinal cells (Poyton et al., 2009). When intestinal I/R occurs, the amount of mtDNA in the circulation also increases significantly. Hu et al. (Hu et al., 2018a) revealed the leading role of mtDNA in the pathogenesis of intestinal I/R injury. A few experimental results have shown that after reperfusion of the ischemic intestine, mitochondrial respiratory function and transmembrane potential are decreased, mitochondrial membrane permeability is increased, and stability is decreased.

During the ischemia or hypoxia period, electron flow through the mitochondrial respiratory chain is inhibited, and ATP synthetase cannot phosphorylate ADP to produce ATP (Grover et al., 2004; Di Lisa et al., 2007). Ischemia or hypoxia also affects ATP hydrolase, which hydrolyzes the remaining ATP (Murphy and Steenbergen, 2008). As a result, ATP levels drop rapidly during ischemia. Mitochondria are important sources of oxidative stress in intestinal I/R. Excessive ROS are produced by the electron transport chain, mitochondrial outer membrane proteins, and other mitochondrial proteins. Under physiological conditions, superoxide produced by electron transport chain complexes I and III is neutralized by SOD. However, in ischemia, mitochondrial complex I superoxide leakage increases, breaking the dynamic balance between cell oxidation and antioxidants and thus aggravating cell damage (Lee et al., 2012; Dan Dunn et al., 2015). During ischemia, the mitochondrial permeability transition pore (mPTP) is inhibited by acidosis and is at rest. I/R induces calcium overload in mitochondria, and the production of ROS causes the mPTP to open (Di Lisa et al., 2009; Ong and Gustafsson, 2012; Di Lisa et al., 2017). Thus, molecules with small molecular weights can pass through this pore, and many H⁺ ions enter the mitochondrial matrix, thereby dissipating the mitochondrial membrane potential, uncoupling the electron transport chain, and inhibiting ATP synthesis (Baines, 2010). At the same time, water seeps into the organelles, causing them to swell and rupture.

When the blood supply to the ischemic organs is restored, a large amount of oxygen influx increases the overproduction of ROS. In recent years, it has been increasingly recognized that RNS also contribute to I/R injury (Duan and Kasper, 2011; Kvietys and Granger, 2012; Raedschelders et al., 2012). ROS refer to free radicals and non-free radicals with relatively strong oxidation and reduction properties, such as superoxide anions (O₂ ⁻), hydrogen peroxide (H₂O₂), and hydroxy free radicals (OH⁻). RNS is a series of complexes produced by NO metabolism, with NO as the center, including peroxynitrite anion (ONOO⁻), nitrate anion (NO⁻), nitrogen dioxide (NO₂), and others. The effects of ROS and RNS are related to their concentrations in vivo. At moderate levels, they act as mediators in signal transduction. However, when their concentrations increase markedly, these species are formidably destructive to lipids, proteins, nucleic acids, and the extracellular matrix. Reactive nitrogen and oxygen species (RNOs) promote reperfusion injury by altering the structure or function of macromolecules, disrupting or activating signal cascades, stimulating the production and release of proinflammatory mediators in various cell types, and inducing the expression of adhesion molecules.

TLR-9 is a protein receptor encoded by the TLR-9 gene, which is mainly expressed in immune cells such as monocytes, macrophages, and dendritic cells. It is highly conserved and mainly recognizes the DNA of bacteria and viruses (Hemmi et al., 2000). MtDNA is composed of unmethylated CpG dinucleotides and is released when mitochondria are damaged. TLR-9 is located in the endoplasmic reticulum and can be activated by CpG DNA (Barbalat et al., 2011). MtDNA is a major type of DAMP that recognizes TLR-9 of immune cells and activates the body’s innate immune response (Kausar et al., 2020). After the released mtDNA recognizes TLR-9, it induces a strong inflammatory response in the body (Wei et al., 2015). MtDNA binds to TLR-9, recruits myeloid differentiation factor 88 (MyD88), activates MAPK and NF-kB, and induces secretion of proinflammatory cytokines (Riley and Tait, 2020). Zhang et al. observed that mtDNA is released into the circulation during SIRS and activates TLR-9 on neutrophils (Zhang et al., 2010a; Zhang et al., 2010b). Various studies have shown that there is a strong correlation between the levels of mtDNA and TLR-9 and that increasing the degradation of mtDNA can reduce the inflammatory response that depends on TLR-9 (Oka et al., 2012). A few studies have shown that intravenous injection of damaged mitochondrial fragments containing a large quantity of mtDNA can stimulate the systemic inflammatory response. Knocking out the MyD88 gene or TLR-9 gene in rats or using TLR-9 antagonists significantly reduces this phenomenon. The significance of TLR9-MyD88 signaling also provides a theoretical basis for inhibiting the systemic inflammatory response. In addition, mtDNA can promote the inflammatory response after I/R injury via TLR9. When cells are hypoxic, mtDNA is complexed with high-mobility group protein B1 (HMGB1) and can autonomously bind to TLR9 to enhance inflammation (Liu et al., 2015). Oxidative mtDNA has been shown to trigger the TLR9 pathway, and oxidative mtDNA released by neutrophils induces plasmacytoid DCs (pDCs) to produce type I interferon (Caielli et al., 2016). Mark et al. reported that the release of mtDNA and TFAM after cell injury, which leads to TLR9-dependent interferon secretion, plays a key role in regulating the sterile immune response (Julian et al., 2013).

The NLRP3 inflammasome is a kind of N-like receptor (NOD-like receptor, NLR) that is composed of NLRP3, an adaptor protein (ASC), and aspartic protease-1 (Caspase-1). It is a kind of pattern recognition receptor (PRR) in the cell membrane. PRRs can recognize related pathogenic microorganisms. Abnormally activated NLRP3 recruits and activates caspase-1, resulting in the release of IL-1 and IL-18 into the extracellular environment and leading to progression of I/R damage (Guo et al., 2016). In 2011, it was first reported that mtDNA facilitates the activation of NLRP3 inflammation, and many reports have since reinforced the idea that mitochondrial damage and mtDNA release are amplified by activation of NLRP3 inflammation. However, a recent study by Shimada et al. has suggested that NLRP3 may not enhance mitochondrial DNA release but rather stabilize mtDNA in the cytoplasm (Yu et al., 2014; Bronner et al., 2015). Studies have confirmed that NLRP3 is widely present in the epithelial cells of the intestinal tissue, and the NLRP3 inflammasome is activated to participate in inflammatory injury of the intestine. Generally, Caspase-1 exists in an inactive form in the body, and the NLRP3 inflammasome mediates its activation (Tsutsui et al., 2010). MtDNA can directly activate the NLRP3 inflammasome (Huo et al., 2013). Abnormal recruitment of NLRP3 activates Caspase-1, and cells produce mature IL-1β and IL-18, triggering a specific cell death mode called pyroptosis (Guo et al., 2015). In addition, NF-kB can enhance the expression of NLRP3 and promote the upregulation of NLRP3 receptor protein expression. NF-kB plays a key role in regulating proinflammatory factors (Taniguchi and Karin, 2018). TLRs can activate the NF-kB pathway, enhance the expression of NLRP3, and participate in intestinal inflammatory damage. Yang et al. found that after rat intestinal I/R, the expression of p-NF-kB p65, NLRP3, Caspase-1, and inflammatory factors is increased (Yang et al., 2020). This suggests that intestinal I/R may be related to the NF-kB/NLRP3 pathway.

The cGAS-STING pathway regulates the production of type I interferons. STING can be activated by its DNA, which induces the production of type I interferon in a STING-dependent manner (Schoggins et al., 2014). The cGAS enzyme is a type of cytoplasmic DNA that activates STING to induce an innate immune response by producing cGAMP. STING then binds and activates TANK-binding kinase 1 (TBK1). TBK1 phosphorylates IRF3, facilitates its dimerization, and shifts to the cell nucleus, resulting in a type I interferon response (Storek et al., 2015; Chen Q. et al., 2016). Cyclic GMP-AMP synthase (cGAS) is a DNA pattern recognition receptor that can recognize DNA to trigger host innate immunity. MtDNA released by damaged cells is an effective ligand that transmits signals through cGAS (Fang et al., 2016). After cGAS recognizes DNA, it catalyzes the synthesis of cyclic dinucleotides (cyclic GMP-AMP, cGAMP). CGAMP combines with the adaptor protein STING (stimulator of interferon) to activate the cGAS-STING signaling pathway and promote the expression of type I interferon, thereby regulating innate immunity (Sun et al., 2013). The STING pathway activates TBK1 to induce phosphorylation of both the IRF3 and NF-kB pathways, and the expression of IFNs (IFNα and IFNβ) and TNF-α increases (Ishikawa and Barber, 2008). Both IFNs and TNF-α can trigger necroptosis of intestinal epithelial cells (Wallach et al., 2016). Necroptosis can promote intestinal barrier dysfunction after intestinal I/R, and infection can significantly aggravate intestinal I/R injury (Victoni et al., 2010; Mittal and Coopersmith, 2014). STING plays an important role in regulating the homeostasis and integrity of the intestinal barrier (Fischer et al., 2017; Canesso et al., 2018). In the gastrointestinal mucosal system, mtDNA is released when mitochondrial damage is caused by ischemia or hypoxia. It then activates the STING signaling pathway to stimulate the production of inflammatory factors. STING is an important molecule for cytoplasmic DNA to activate the innate immune response. Both endogenous and exogenous DNA are recognized by STING and mediate its downstream inflammatory signals. The cGAS-STING signaling pathway can be regulated by adjusting the phosphorylation and ubiquitination of STING. Mitochondrial oxidative stress induces mitochondrial DNA release after intestinal I/R and subsequently promotes intestinal I/R injury (Hu et al., 2018a). Intestinal I/R injury is an important pathway for acute intestinal barrier damage. The breakdown of the intestinal barrier mediated by STING results in severe sepsis (Hu et al., 2019b). MtDNA induces intestinal necroptosis, further promoting intestinal I/R damage. In addition, mtDNA-mediated STING signaling triggers necroptosis via synergistic IFN and TNF-α signal transduction (Zhang et al., 2020).

Through the above signaling pathways, mtDNA induces inflammatory activation, initiates SIRS, and damages the intestinal mucosal system through the circulatory system (Hu et al., 2018a).

The intestinal mucosal barrier is mainly composed of a mechanical barrier, an immune barrier, and a biological barrier. The various parts interact to protect the body. MtDNA release, inflammatory factors, bacterial toxin displacement, and other factors can cause intestinal I/R injury. This in turn destroys the intestinal barrier. Therefore, preventing intestinal I/R injury can greatly reduce the functional damage of the intestinal mucosal barrier. Increasing the tolerance of organs or tissues to ischemia and reperfusion may be an important method of preventing reperfusion injury, especially during major surgeries directly related to ischemia and reperfusion (Hausenloy and Yellon, 2016). Current measures to prevent intestinal I/R mainly include ischemic preconditioning (IPC) and ischemic postconditioning (IPO) (Camara-Lemarroy, 2014; Heusch, 2015). A meta-analysis has revealed that ischemic preconditioning significantly improves tissue tolerance to ischemia (Salvador et al., 2016). Postischemic treatment can significantly reduce the degree of intestinal I/R injury (Jonker et al., 2016). IPC is a clinical application of cell protection for key organs (Li et al., 2013; Li et al., 2014b).

IPC involves short-term ischemia and reperfusion of the intestinal tissue before the expected ischemia period, which can initiate the endogenous protective mechanism to deal with the subsequent ischemia for a prolonged period and reduce the damage to tissues and organs. This is adaptive protective mechanism for a transient ischemic period (Miranda et al., 2019). Many studies have shown that IPC can reduce intestinal tissue damage and alleviate SIRS. Hotter et al. (Hotter et al., 1996) elucidated the protective effect of IPC against intestinal I/R. IPC can reduce intestinal I/R by reducing oxidative stress and participating in signal transduction (Avgerinos et al., 2010; Mallick et al., 2010; Xing et al., 2014). IPC attenuates neutrophil-endothelial cell adhesion cascade reactions; reduces intestinal oxidative damage (Ferencz et al., 2004); and protects the intestine from I/R damage by releasing mast cell degranulation-mediated carboxypeptidase A (Xing et al., 2014), inhibiting heme oxygenase (Mallick et al., 2010), and regulating arachidonic acid cascade reactions (Avgerinos et al., 2010). IPC reduces the release of proinflammatory cytokines (Wang et al., 2015). Results obtained by Ji, Y.Y, et al. (Ji et al., 2015) have shown that IPC can reduce the levels of MPO and TNF α, inhibit the expression of ICAM-1 and VCAM-1, and decrease the activity and expression of NF-kB to protect the intestine from I/R injury. Although the protective effect of IPC on the intestinal tract has been well established, IPC has not been widely used in the clinic. More clinical trials are needed to further study the use of IPC in the intestine.

IPO refers to the use of a few short reperfusion and re-ischemia cycles after intestinal tissue ischemia and before recovery of perfusion, which can increase tissue resistance to I/R injury and protect intestinal tissue. It is a safe and feasible method in the clinic. Studies have revealed that ischemic posttreatment can effectively improve the morphology and respiratory function of intestinal mucosal cell mitochondria and increase mitochondrial transmembrane potential, suggesting that the protective effect of ischemic posttreatment may be related to mitochondria. Cheng, C.H, et al. (Cheng CH. et al., 2013) demonstrated the protective effect of IPO against intestinal I/R injury in rats. IPO was found to alleviate intestinal mucosal injury and oxidative stress by regulating mPTP formation to ameliorate intestinal I/R injury (Cheng CH. et al., 2013). The formation of the mPTP and changes in mitochondrial membrane potential are key determinants of cell fate in I/R injury (Halestrap et al., 2002). Therefore, inhibition of mPTP formation is critical. In addition, apoptosis is an important mechanism of I/R-induced intestinal cell death. IPO reduces intestinal injury in rat models by inhibiting apoptosis of intestinal mucosal cells (Chu et al., 2015). This effect is mediated by the JAK/STAT pathway, which plays an important role in intestinal I/R injury (Wen et al., 2012). In a rat model of intestinal I/R, IPC has been found to induce upregulation of miR-21 through HIF-1α, inhibit apoptosis, and lead to downregulation of the apoptotic mediators PDCD4 and Fas-L, thereby mitigating intestinal I/R injury (Jia et al., 2017). Both miR-21 and HIF-1α are antiapoptotic miRNAs and factors that are upregulated during hypoxia, and further increases in the levels of these molecules during intermittent hypoxia may be responsible for the protective mechanism.

Remote ischemic preconditioning (RIPC) involves transient, repeated nonlethal ischemic treatment of organs or limbs to protect the distal organs/limbs from I/R injury (Hausenloy and Yellon, 2008). In addition to neurogenic pathways and systemic anti-inflammatory responses, the release of humoral mediators stimulated by RIPC may play a key role in its effects (Hausenloy and Yellon, 2008; Pickard et al., 2015). Several researchers have shown that RIPC reduces cell death from I/R injury in different organs (Cheng et al., 2014; Hu et al., 2016; Xu et al., 2017) and increases the antioxidant capacity of the tissue to mediate organ protection (Zitta et al., 2015; Jin et al., 2016; Motomura et al., 2017). Several studies have shown the beneficial effects of RIPC on the intestine (Candilio et al., 2013). IIn a rat model, Dickson et al. showed that RIPC increased intestinal tolerance to hypoxia after I/R injury. Saeki et al. found that in a rat model of small intestine transplantation, three cycles of 15 min of RIPC reduced intestinal injury (Toldo et al., 2018), while a single cycle had no significant protective effect on the hindlimbs (Yue et al., 2012). The potential mediators of RIPC include HIF-1α, ADAMTS1, Cited2, and cytochrome C, but the interactions of these molecules require further confirmation (Hummitzsch et al., 2019).

ATP deficiency during intestinal I/R is the main cause of intestinal mucosal injury due to intestinal cell death. Providing enough ATP can ameliorate the disorder of the internal environment and maintain cell membrane stability. Mueller et al. (Mueller et al., 2018) injected creatine supplements into the intestinal lumens of SD rats to provide ATP for the ischemic intestine and observed that intestinal I/R could alleviate intestinal mucosal injury. Hansen et al. (Hansen et al., 2016) found that elevating mitochondrial levels in ischemic tissue can reduce intestinal mucosal damage induced by I/R. It may be useful to inhale two standard atmospheric pressures of oxygen and arterial infusion fructose diphosphate (FDP) during ischemia. This therapy reduces intestinal tissue damage by improving cellular energy metabolism and maintaining the integrity of the intestinal mucosal structure and function.

In many animal experiments, the use of antioxidants can significantly reduce I/R-induced tissue injury, and antioxidant free radicals are important treatments for intestinal I/R injury. Akgür et al. (Akgür et al., 1996) demonstrated that allopurinol inhibits the production of oxygen free radicals and attenuates intestinal mucosal injury after I/R injury. Mitochondrial oxidative damage may induce the release of mtDNA, activate pattern recognition receptors, and damage the intestinal barrier. Therefore, mitochondrial antioxidants can effectively prevent damage to intestinal barrier function. Recent studies have shown that pretreatment with the mitochondrial-targeted antioxidant MitoQ protects mitochondria from oxidative damage, reduces ROS production and stabilizes mitochondrial transcription factor A (TFAM) and that MitoQ activates the Nrf2/ARE pathway. MitoQ also prevents oxidative stress from damaging mtDNA, ultimately enhancing the integrity of the intestinal barrier (Hu et al., 2018b). Commonly used antioxidants include ATP, superoxide dismutase, glutathione, melatonin, vitamin C, vitamin E, and pyruvic acid.

When intestinal I/R injury occurs, the body initiates an inflammatory response. White blood cells are activated and adhere to the inner walls of blood vessels with microcirculation disorders, further leading to tissue and organ damage (Gordeeva et al., 2017). Gordeeva et al. (Gordeeva et al., 2017) found that inhibiting leukocyte activation, hindering leukocyte adhesion molecule synthesis, and reducing leukocyte-endothelial adhesion can reduce intestinal I/R injury. At present, there are leukocyte chemotactic drugs, such as PAF and anti-CD11 monoclonal antibodies.

Glucocorticoids (GCs) have strong effects on inflammatory and immune processes. They are commonly used to treat autoimmune and chronic inflammatory diseases (Cain and Cidlowski, 2017; Ronchetti et al., 2020). GCs are immunomodulatory, and acute exposure to GCs activates the immune system, whereas long-term use of GCs may lead to immunosuppression (Dhabhar, 2002). GCs exert anti-inflammatory effects by inhibiting proinflammatory cytokines and transcription factors and inhibiting anti-inflammatory gene activation (Ronchetti et al., 2015). Other studies have reported proinflammatory effects of GCs, such as induction of the expression of the NLRP3 inflammasome (Ronchetti et al., 2018). A large number of glucocorticoid receptor transcriptional effects contribute to the anti-inflammatory and immunomodulatory effects of GCs (Cain and Cidlowski, 2017). In the early stages of inflammation, circulating GCs can modulate cytokines involved in the immune response (Ji et al., 2016; Ronchetti et al., 2017). Therefore, GCs are widely used in the treatment of inflammatory diseases.

Synthetic GCs, such as prednisolone, betamethasone, and dexamethasone, are now commonly used clinically (Ronchetti et al., 2018). However, long-term GC use causes a wide range of adverse reactions (Ayroldi et al., 2014; Cain and Cidlowski, 2017), and rational use of GCs requires a deeper understanding of GC interactions in various systems. In addition, alternative molecules with the same efficacy as GCs with fewer side effects, such as glucocorticoid-induced leucine zipper (GILZ), have been shown to regulate immune cell activation and promote anti-inflammatory phenotypes (Berrebi et al., 2003; Ronchetti et al., 2020).