Quercetin: A Flavonoid with Potential for Treating Acute Lung Injury

Introduction

In the ICU, acute lung injury (ALI) is a common syndrome that can lead to acute respiratory distress syndrome (ARDS).¹ According to recent statistics, the development of ALI/ARDS in the ICU is currently associated with mortality rates of 25–40%, and these rates are increasing. Both intrapulmonary and extrapulmonary factors can cause ALI/ARDS.^2,3 The pulmonary factors include the consequences of pneumonia, pulmonary contusion, hyperoxia, smoke inhalation, phosgene, inhalation of gastric contents, smoking, drowning, fat embolism, lung transplantation, radiation, chemical poisoning, and inappropriate mechanical ventilation. Extrapulmonary factors affecting ALI/ARDS encompass sepsis, severe shock, pharmacological agents, blood transfusions, burns, acute pancreatitis, race, hypoxia, alcoholism, advanced age (>65 years), acute exacerbations of chronic obstructive pulmonary disease (AECOPD), disseminated intravascular coagulation (DIC), and hyperthermia (Figure 1).^4–7 In particular, a classification mechanism for ALI is not present. This paper categorizes ALI into various types, including those caused by pneumonia, trauma, inhalation, mechanical ventilation, sepsis, pulmonary ischemia/reperfusion injury, hypoxia, pharmacological agents, blood transfusions, severe acute pancreatitis, toxins, radiological treatments, and fever (Figure 1). The pathogenesis of ALI/ARDS is complex, primarily encompassing inflammation,⁷ oxidative stress,⁸ apoptosis,⁹ ferroptosis,¹⁰ autophagy,¹¹ and fibrosis.¹² The development of ALI can be prevented by reducing or blocking these factors. The pathogenesis of ALI/ARDS is complex, primarily encompassing inflammation,⁷ oxidative stress,⁸ apoptosis,⁹ ferroptosis,¹⁰ autophagy,¹¹ and fibrosis.¹² The development of ALI can be prevented by reducing or blocking these factors (Figure 1). Treatment of ALI/ARDS is mainly symptomatic supportive therapy, including rehydration, anti-infection treatment, and iratory, nutritional, and organ function support.^5,13 However, the overall therapeutic effect is inadequate and fails to treat the underlying source of the disease. The discovery of specialized drugs for ALI/ARDS is thus critically needed. ALI therapy has been the subject of numerous studies during the last several decades. Quercetin has drawn interest because of its wide variety of bioactivities, pharmacological effects, and outstanding therapeutic effects on ALI.

Figure 1 Causes and classification of acute lung injury.

Flavonoids are abundant in plants, where phytochromes mediate light radiation to stimulate their synthesis. They are low molecular weight metabolites of naturally occurring plant polyphenols, which are primarily found in vascular plants and have various pharmacological and biological effects.¹⁴ Quercetin, one of the most powerful antioxidants among flavonoids, also known as oak extract and quercetin flavonoid, is one of the most powerful flavonoid antioxidants and is a secondary metabolite synthesized by most plants, including ancient plants such as ferns. Quercetin was initially identified in 1936 by Hungarian physiologist Albert Szent-György. Quercetin occurs in the stems, skins, flowers, leaves, buds, seeds, and fruits of plants, primarily as glycosides, and can be extracted through acid hydrolysis. Quercetin is present in various vegetables and fruits, including onions, cabbage, peppers, tomatoes, grapes, apples, mangoes, and plums. Furthermore, it is a primary component in over a hundred herbal medicines derived from medicinal plants, such as winterflower, mulberry parasol, prickly ginseng, astragalus, and ginkgo biloba.^15–17 Quercetin is a flavonoid present in dark-colored, nutrient-dense fruits and vegetables.

Quercetin can inhibit the polar transport of certain plant hormones, such as auxin. Its formula is C₁₅H₁₀O₇, with a molecular weight of 302.24 g/mol. Quercetin shows complete insolubility in cold and hot water while demonstrating high solubility in alcohol and lipids.^18–20 The compound features a benz(γ)-pyranone structure characterized by a C6-C3-C6 carbon skeleton comprising two benzene rings linked by a three-carbon pyran ring. The quercetin molecule has a variety of biological activities and pharmacological effects due to its four phenolic hydroxyl groups, one enolic hydroxyl group, and one carbonyl structure.²¹

As a drug, Quercetin is safe and reliable with few side effects (Table 1).²² For example, in an experimental study on quercetin toxicity, it was found that high doses of quercetin extract in rats (6 g/kg) did not induce organ damage or death. Subacute tests revealed no significant differences in histomorphology, blood biochemistry, or blood counts.²³ Further, after taking 5000 mg of quercetin orally every day for 28 days in succession,²⁴ individuals with chronic hepatitis C did not experience any negative side effects, according to clinical studies. In 2010, Quercetin received GRAS approval from the US The Food and Drug Administration (FDA) has approved certain substances in beverages, cereal products, pasta, processed fruits and juices, and gummies, permitting production from natural sources. Quercetin received approval for use in antioxidants, anti-allergy drugs, and as a supplement for COVID-19 DELTA variants.^25,26 Quercetin is used as a food additive in Japan and Korea. A review by Ding et al thoroughly summarized the safety and reliability of Quercetin based on results from Phase I and Phase II clinical trials. Individuals with conditions such as chronic obstructive pulmonary disease (COPD), tuberculosis, neo-coronary disease, cardiovascular disease, gastro-oesophageal reflux disease, hepatitis C, Alzheimer’s disease, rheumatoid arthritis, age-related macular degeneration, nephropathy did not experience any adverse reactions following Quercetin application.²⁷

Table 1 Bioactivity and Pharmacological Effects of Quercetin

The chemical structure of Quercetin confers various pharmacological effects.²³ The o-diphenol structure of the quercetin molecule and the hydroxyl group at C3 demonstrate significant reducing properties. This enables the scavenging of reactive oxygen species (ROS) radicals, chelation of metal ions, inhibition of oxidized low-density lipoprotein (Ox-LDL), modulation of signal transduction pathways, and regulation of glutathione (GSH) levels, enzyme activities, and antioxidant substances, thereby enhancing resistance to oxidative stress.^28–30 Quercetin can also inhibit the release of inflammatory factors and mediators, modulate inflammatory pathways, and thus play an anti-inflammatory role.³¹ Quercetin influences the cell cycle in tumor cells, impacts tumor-related signal transduction pathways, and promotes tumor cell apoptosis, which inhibits cancer proliferation and metastasis.³² It can inhibit histamine release and the formation of antigen-specific IgE antibodies, reduce leukotriene production, and improve Th1/Th2 balance, thereby exerting antiallergic effects.³³ Furthermore, it increases blood flow and energy metabolism in the brain, promotes neuronal regeneration, and inhibits neuroinflammation, resulting in cerebral neuroprotective effects.³⁴ In addition to the above pharmacological effects, Quercetin has antiviral, antibacterial, anti-fibrotic, anti-focal death, anti-obesity, antidepressant, and anti-aging properties, while inhibiting apoptosis, autophagy, and platelet aggregation, regulating the immune system, protecting against hyperlipidemia, hypertension, hyperglycemia, liver damage, and coronary artery disease.³⁵ Quercetin shows a wide array of pharmacological effects, and its lipophilicity facilitates the crossing of cell membranes, activating various intracellular signaling pathways.³⁶ This compound treats cardiovascular,³⁷ digestive,³⁸ renal,³⁹ endocrine,⁴⁰ nervous system,⁴¹ and respiratory diseases.⁴² Multiple studies demonstrate that Quercetin demonstrates significant therapeutic effects on various types of acute lung injury, including those caused by sepsis, radiological treatments, paraquat toxicity, inhalation, hypoxia, severe pancreatitis, pneumonia, and ischemia/reperfusion.

Quercetin exhibits potential therapeutic effects for ALI, attributable to its source, structural characteristics, safety profile, and pharmacological properties. However, a thorough investigation into its application for treating ALI has not been conducted. This study systematically reviews research on Quercetin and ALI published over the last decade, evaluating advancements in the field and proposing novel treatment strategies for ALI.

Progress in Research on the Use of Quercetin in Various Types of Acute Lung Injuries

Use of Quercetin for Treating Septic Lung Injury

Sepsis can lead to significant lung injury. Oxidative stress, inflammatory cells, and mediators primarily contribute to this acute disorder. Controlling inflammation and oxidative stress is essential for preventing acute lung injury during septic lung injury.^43,44 Furthermore, ferroptosis and efferocytosis are involved.^45,46 Quercetin has been thoroughly investigated as a therapeutic agent for septic lung injury due to its ability to promote efferocytosis and mitigate inflammation, oxidative stress, and ferroptosis (Table 2).

Table 2 Results of in vitro and in vivo Studies on the Treatment of Septic Lung Injury with Quercetin

Inhibition of the Inflammatory Response

Cyclic adenosine monophosphate (cAMP) is the most widely used second messenger. It is involved in regulating various physiological processes, including inflammation, calcium transport, cell growth, and apoptosis.⁵⁸ The cyclic adenosine monophosphate-activated exchange protein (Epac) operates downstream of cAMP and is involved in multiple effector and signal transduction mechanisms. cAMP can enhance the regulation of Epac. The cAMP/Epac signaling system modulates inflammation,⁵⁹ and its activation is essential for mitigating septic lung injury.⁶⁰ Wang et al conducted a study demonstrating that Quercetin activates the cAMP/Epac pathway, leading to the inhibition of inflammatory cytokine release in mouse lung tissue, the blockage of neutrophil recruitment, and a reduction in pathological changes linked to lung injury. In in vitro investigations using LPS-induced pulmonary epithelial cells (MLE-12), Quercetin was observed to modulate the cAMP/Epac pathway, inhibiting the production of chemokines from keratinocytes, therefore mitigating inflammation-induced cell damage and improving cell survival.⁴⁴

Sirtuin 1 (SIRT1) is a deacetylase implicated in inflammation, oxidative stress, and apoptosis.⁶¹ SIRT1 inhibits the activation of the NLRP3 inflammasome, which triggers the production of IL-1β, IL-18, and HMGB1, therefore initiating and amplifying the innate immune response.⁶² Pyruvate kinase M2 (PKM2) is a crucial enzyme that regulates aerobic glycolysis, lactate synthesis, and metabolic transformation. The inflammatory response activates the PKM2 dimer, leading to its translocation to the nucleus, where it phosphorylates and activates transcription factors such as Nrf2, STAT3, and NF-κB, thereby regulating gene expression.⁶³ In a mouse model of septic lung injury, Quercetin increased SIRT1 expression in lung tissue, inhibited NLRP3 inflammasome activation, and reduced the release of pro-inflammatory factors (TNFα, IL-1β, and IL-6), preventing the up-regulation of nuclear PKM2 in the lung. Overexpression of SIRT1 inhibited the nuclear PKM2 accumulation and NLRP3 activation, resulting in improved anti-inflammatory effects of Quercetin. Inhibition of SIRT1 expression resulted in increased NLRP3 activation and nuclear accumulation of PKM2, therefore, preventing the anti-inflammatory effects of quercetin. These results suggest that Quercetin activates the SIRT1/PKM2/NLRP3 pathway, reducing the inflammatory response and alveolar wall damage, thus inhibiting septic lung injury.⁴⁷

An essential enzyme in heme catabolism, HO-1 is associated with several in vivo anti-inflammatory molecular mediators. HO-1 has anti-inflammatory and anti-oxidative stress actions by activating inflammatory and oxidative stress signaling pathways in cells and tissues under stress and protecting cells from oxidative damage.⁶⁴ Research has indicated that inflammatory pathways mediated by HO-1 play a crucial role in septic lung injury. Quercetin increased HO-1 expression in the lungs of a septic lung injury mouse model, reducing the release of inflammatory factors and the lung wet-to-dry ratio in BALF. It increased the HO-1 expression in lung AMJ2-C11 cells stimulated by LPS in an in vitro experiment. It decreased the cells’ inflammatory response and improved their survival rate by preventing the release of pro-inflammatory molecules (TNF-α, IL-1β, and IL-6). When applied in reverse, the HO-1 inhibitor’s protective impact on cells was diminished.⁴⁸

In addition to regulating the above pathways to inhibit the inflammatory response, Quercetin can also regulate the Notch1,⁵⁴ SCAP/SREBP2/NLRP3,⁵⁵ PTEN/β-catenin, AKT/GSK-3β,⁵³ TLR4/Myd88,⁵⁶ and Nrf-2/ARE pathways⁵⁷ to reduce the release of inflammatory factors and mediators, thereby exerting anti-inflammatory effects and thus attenuating septic lung injury.

Inhibition of Ferroptosis

Ferroptosis is a form of cell death characterized by iron accumulation and lipid peroxidation.⁶⁵ Disruption of intracellular iron homeostasis can trigger the Fenton reaction, leading to lipid peroxidation and inducing cell death. In septic lung injury, disrupted iron metabolism, lipid peroxide accumulation, and reduced lung antioxidant capacity contribute to endothelial damage in lung capillaries, increased vascular permeability, and reduced effective ventilation, ultimately resulting in intractable hypoxemia.⁶⁶ Therefore, inhibiting ferroptosis is another way to treat septic lung injury. SIRT1 is a deacetylase that regulates various transcription factors to exert anti-oxidative stress, anti-inflammatory, anti-apoptotic, and anti-aging effects. It depends on Nrf2 activation, which induces its translocation from the cytoplasm to the nucleus, resulting in the related protein expression. Activation of the SIRT1/Nrf2 signaling pathway reduces ROS production and activates antioxidant production, thus attenuating iron death.⁶⁷ Gpx4, a downstream target of Nrf2, is a mammalian membrane peroxidase critical for ferroptosis. In in vivo experiments in mice, Quercetin up-regulated SIRT1 activation of the Nrf2/Gpx4 pathway to inhibit ferroptosis, reducing the TNF-α, IL-6, and IL-1β levels in the BALF and consequently attenuating the inflammatory response of the lungs.⁵⁰ In in vitro experiments, Quercetin modulated the Sirt1/Nrf2/Gpx4 pathway to inhibit ferroptosis, thus improving the proliferative capacity of alveolar epithelial cells and the alveolar epithelial barrier. However, when a SIRT1 inhibitor was added to both in vitro and in vivo experiments, the protective effect of Quercetin on the lung was reversed. The Nfr2/HO-1 pathway plays an essential role in oxidative stress, with Nrf2 participating in the antioxidant response and HO-1 contributing to cellular protection from oxidative damage.⁴⁹ In a study by Li et al. Quercetin was also found to activate the Nfr2/HO-1 pathway to inhibit ferroptosis in rat lungs, thereby attenuating oxidative stress and the inflammatory response and consequently reducing septic lung injury.⁶⁸

Inhibition of Oxidative Stress

Oxidative stress is caused by the imbalance between the reactive oxygen/nitrogen species and the antioxidant defence mechanism, resulting in excessive ROS production and an over-oxidized state. This in turn damages biomolecules, such as nucleic acids, lipids and proteins of the tissue cells.⁶⁹ In septic lung injury, the lungs produce excessive ROS, disrupting the balance between oxidative and antioxidant systems. This leads to lipid peroxidation, mitochondrial DNA damage, pulmonary oedema, and irreversible lung injury.^70,71 Gerin et al established a septic lung injury model by cecum ligation and puncture in rats, showing that early administration of Quercetin reduced the levels of oxidative stress markers, such as xanthine oxidase (XO), nitric oxide (NO), and malondialdehyde (MDA), and increased the levels of antioxidant enzymes in lung tissues, leading to a reduction in oxidative stress and consequently reduced production of inflammatory factors in the lungs.⁴³ In a study by Sang et al using in vitro experiments with LPS-stimulated ML-12 cells, Quercetin was found to modulate the SIRT1/AMPK pathway to inhibit both endoplasmic reticulum stress and oxidative stress levels in cells, which was manifested by a decrease in the expression of PDI, CHOP, GPC78, ATF6, PERK, and IRE1A, together with enhanced mitochondrial function, and increased levels of matrix metalloproteinase (MMP) and superoxide dismutase (SOD) while reducing the production of ROS and MDA, which in turn reduced the release of inflammatory factors in the cells. In in vivo experiments, Quercetin could also regulate the SIRT1/AMPK pathway to reduce oxidative stress and inflammatory damage in mouse lungs, thus alleviating septic lung injury.⁵¹ In a similar study, Quercetin reduced myeloperoxidase (MPO) activity and increased the levels of MDA in mouse lungs, thereby reversing oxidative stress; Quercetin also reduced the expression of COX-2, HMGB1, and iNOS expression and NF-κB p65 phosphorylation, inhibited the release of inflammatory factors (TNF-α, IL-6, NO), improved the permeability of the lungs, and reduced the levels of inflammatory cells in the BALF.⁵² Thereby reducing the inflammatory response in the lungs and alleviating lung injury in the mice. In another in vivo experiment, Quercetin modulated the PTEN/β-catenin and AKT/GSK-3βpathways to reduce oxidative stress levels in the lungs, alleviating lung injury.⁵³ In conclusion, Quercetin can reduce oxidative stress and increase the activity of antioxidant enzymes during septic lung injury, thereby inhibiting lung injury.

Enhancement of Alveolar Macrophage Efferocytosis

When acute inflammation in the lungs subsides, alveolar macrophages can phagocytose the apoptotic inflammatory cells and, at the same time, promote the recovery of lung epithelial and endothelial function and the repair of lung tissue structure, a phenomenon known as efferocytosis. Efferocytosis of alveolar macrophages is essential for alleviating ALI as it prevents excessive inflammatory responses and assists in the reconstruction of lung tissue to attenuate lung injury.⁷² The peroxisome proliferator-activated receptorγ(PPARγ)/liver X receptorα(LXR-α) signaling pathway is key to the regulation of inflammation and oxidative stress in vivo, and activation of this pathway can effectively inhibit the release of inflammatory mediators and ROS. Among them, the PPARγ-mediated pathway plays a vital role in expressing various cell burial-related factors and regulating efferocytosis.⁷³ In a study by Yang et al, it was found that Quercetin could enhance alveolar macrophage efferocytosis, reduce the serum levels of inflammatory factors, inhibit the development of a cytokine storm, and attenuate the inflammatory response in lung tissues and consequent pathological injury in an LPS-induced rat model of ALI, the mechanism of which was related to activation of the PPARγ/LXR-α signaling pathway.⁴⁵ Therefore, Quercetin can reduce septic lung injury by regulating the PPARγ/LXR-αaxis to increase lung tissue efferocytosis.

Inhibition of Cellular Pyroptosis

Cellular pyroptosis is an immune response triggered by pathogen detection, causing cell membrane rupture and the release of cytoplasmic contents and inflammatory mediators.⁷⁴ This in turn leads to inflammation and partial loss of tissue or organ function. NLRP3 inflammasome activation is an essential pathway in the occurrence of pyroptosis,⁷⁵ and its inhibition prevents the development of pyroptosis, as demonstrated by Shi et al. Inhibition of NLRP3 inflammasome pathway inhibited cellular pyroptosis, thereby attenuating PM2.5-induced lung injury.⁷⁶ NLRP3 inflammasome-mediated cellular pyroptosis also plays a key role in septic lung injury, making targeting NLRP3-cellular pyroptosis and its related signalling pathways critical. Quercetin inhibited the activation of NLRP3 inflammasome, reducing lactate production and lung pro-inflammatory factor release and ameliorating lung tissue injury, thus attenuating septic lung injury in mice.⁴⁷

Quercetin in the Treatment of Radiological Lung Injury

Radiation-induced lung injury (RILI) is a common complication of radiotherapy for nasopharyngeal, cervical, and esophageal cancers, among others.⁷⁷ Inflammation and oxidative stress play essential roles in the pathogenic process of RILI.⁷⁸ The NF-κB and MAPK pathways are easily activated by ultraviolet light or radiation, leading to the expression of pro-inflammatory mediators, which promote the production of large amounts of inflammatory factors by macrophages.^79,80 In a mouse model of RILI, Quercetin was found to down-regulate expression of the NF-κB complex (NF-κB, p65, IκB-α) and MAPK (SAPK/JNK, P44/P42) pathway proteins, thereby inhibiting the release of inflammatory factors from the lungs and attenuating the pathological changes associated with lung injury. It can thus be concluded that Quercetin can inhibit the NF-κB and MAPK-mediated inflammatory pathways and, therefore, attenuate RILI in mice.⁸¹ Further, Liu et al showed that early intervention using quercetin liposomes in RILI model mice reduced MDA contents in lung tissue, increased SOD and GSH-PX activities, and reduced the proportion of inflammatory cells and HP content in the BALF.Meanwhile, histological examination using HE staining showed suppression of the inflammatory response and reduced fibrosis scores in the lungs. This indicates that Quercetin can inhibit radiation-induced oxidative stress in the lungs, thereby reducing inflammation.⁸² Furthermore, several network pharmacological analyses found that both Houttuynia cordata and Scutellaria barbata could reduce the radiation-induced inflammatory response and thus reduce lung injury; the main pharmaceutical component of these is Quercetin.^83,84 Therefore, Quercetin has an essential role in preventing and treating RILI.

Quercetin in the Treatment of Lung Ischemia-Reperfusion Injury

Lung ischemia-reperfusion injury (LIRI) frequently occurs following procedures such as pulmonary embolism extraction, cardiopulmonary bypass surgery, shock, and lower limb and trunk ischemia-reperfusion.⁸⁵ LIRI can result in pulmonary edema and pulmonary hemorrhage, both of which are closely linked to ARDS. LIRI is a complex condition characterized by a “sterile” inflammatory state. It involves the production of reactive oxygen and nitrogen species, which contribute to endothelial damage. This damage triggers the activation of factors that attract neutrophils, leading to their infiltration. This process creates a vicious cycle that ultimately results in further endothelial and parenchymal damage, as well as fatal edema and impaired gas exchange.⁸⁶ The primary mechanisms associated with LIRI include inflammatory responses and oxidative stress, and targeting these pathways is crucial for LIRI mitigation.⁸⁷ In the study of Liu et al, it was found that quercetin could inhibit the expression of p-IκBα, p-PI3K, p-AKT/AKT, TNF-α, IL-6, IL-1β, and reduce the serum levels of TNF-α, IL-6, and IL-1β in lung tissues, through the establishment of a LIRI mouse model. At the same time, quercetin could also reduce the infiltration of large number of inflammatory cells in the alveolar lumen and lower the lung injury score. It can be concluded that quercetin can regulate the PI3K/AKT/NF-κB-mediated inflammatory pathway and thus inhibit lung injury.⁸⁸ Acid sphingomyelinase (aSMase) is a critical enzyme in sphingolipid biochemistry.⁸⁹ It can be activated during inflammatory conditions, converting sphingolipids to ceramide, a significant player in the inflammatory pathway.⁹⁰ Thus, inhibition of aSMase is beneficial in reducing inflammatory responses. In a rat model of LIRI induced by traumatic shock, Quercetin was observed to inhibit aSMase activation. This led to improved blood gas values, reduced IL-6 levels, and decreased MPO activity in the BALF, ultimately alleviating lung injury stemming from inflammation and oxidative stress.⁹¹

Quercetin in Paraquat-Induced Toxic Lung Injury

The lungs are particularly susceptible to damage in cases of paraquat (PQ) poisoning, as PQ triggers a significant increase in ROS levels in lung tissues.¹² This surge in ROS results in secondary oxidative damage, ultimately leading to acute lung fibrosis. The toxic lung injury caused by PQ is closely linked to both oxidative stress and the development of fibrosis in the lungs. In a laboratory setting using PQ-exposed alveolar A549 cells, it was discovered that Quercetin activated the Nrf2/HO-1 pathway, leading to reduced ROS production and elevated GSH levels, consequently decreasing oxidative stress and ultimately enhancing the survival of alveolar cells damaged by PQ.⁹² Pulmonary fibrosis involves the destruction of alveolar tissues, resulting in damage to the alveolar epithelium, increased fibroblast proliferation and collagen infiltration, and interstitial inflammation. Various cytokines are involved in alveolitis and pulmonary fibrosis, with TGF-β playing a central role.^69,93 Among them, TGF-β1 is the key cytokine in fibrogenesis⁹⁴ and is most closely associated with pulmonary fibrosis. Smad is the key downstream regulator of TGF-β1, and TGF-β1 positively regulates Smad to enhance its fibrogenic role.⁹⁵ Meanwhile, the Akt/mTOR signalling pathway is also crucial in TGF-β-mediated pulmonary fibrosis. Akt can stimulate mTOR to participate in pulmonary fibrosis through phosphorylation of the PH domain at the amino acid terminus.⁹⁶ Therefore, regulating TGF-β1/Smad and Akt/mTOR signalling pathways is essential for inhibiting pulmonary fibrosis. In an in vitro study of PQ-treated lung epithelial cells (MLE-12 cells), Quercetin was found to modulate the fibrotic process mediated by the TGF-β1/Smad and Akt/mTOR signaling pathways, altering the expression of markers of the epithelial-mesenchymal transition (EMT) and inhibiting the onset of fibrosis, resulting in improved cell survival.⁹⁷ A separate investigation into PQ-induced lung injury in rats revealed that Quercetin mitigated oxidative stress in the lungs by lowering MDA levels and enhancing GSH activity and total ROS-scavenging capacity via the up-regulation of HO-1 expression, consequently diminishing fibroblast distribution and collagen infiltration caused by PQ in the lungs.⁹⁸

Quercetin for Treating Inhalation Lung Injury

Hyperoxic Acute Lung Injury

Oxygen therapy is a fundamental intervention for acute and critical patients in the ICU.⁹⁹ However, prolonged inhalation of elevated oxygen concentrations might precipitate hyperoxic acute lung damage (HALI), potentially resulting in bronchopulmonary dysplasia (BPD).¹⁰⁰ Oxidative stress and inflammation are intimately associated with the progression and severity of HALI. Maturu et al found that Quercetin reduced MDA protein adducts in mouse lungs and thus modulated hyperoxia-induced lung antioxidant solubilization by establishing a model of BPD in neonatal mice under hyperoxic conditions. Moreover, Quercetin also modulated the NF-κB pathway to reduce inflammatory cell infiltration in lung tissues and improve alveolarization and vascularized lung structures after hyperoxia exposure.¹⁰¹ This indicates that Quercetin diminishes lung inflammation and enhances alveolization, thereby mitigating HALI and demonstrating efficacy in preventing BPD.Prostaglandin-endoperoxide synthase 2 (PTGS2) plays a crucial role in the synthesis of prostaglandins under pathological conditions. It is recognized as a marker of ferroptosis and participates in the inflammatory cascade that enhances the release of inflammatory mediators. Therefore, targeting PTGS2 is essential for inhibiting ferroptosis.¹⁰² Deng et al conducted a study employing network pharmacology and molecular docking, demonstrating that Quercetin inhibits ferroptosis, thereby reducing lung inflammatory responses. The MAPK/PTGS2 pathway mediated this action. The findings suggest that Quercetin aids in reducing hyperoxia-induced BPD and decelerates the progression of this condition.¹⁰³

Smoke Inhalation Lung Injury

Smoke inhalation lung injury is common after exposure to fire in enclosed environments. The inhalation of smoke can trigger the production of significant amounts of inflammatory mediators, cytokines, and ROS in the lungs, leading to endothelial cell damage. This mechanism encourages the phospholipids and unsaturated fatty acids in the cell membrane to peroxide, which causes oxidative stress and an inflammatory reaction in the lungs, leading to pulmonary edema.¹⁰⁴ For example, quercetin was found to prevent and delay the progression of COPD lesions in an ex vivo model of cigarette smoke-induced COPD by inhibiting smoke-induced oxidative stress and mitigating the short-term changes in lung structure and function caused by cigarette smoke.¹⁰⁵ A recent review indicated that Quercetin can mitigate smoking-induced COPD due to its antioxidant, anti-inflammatory, and immunomodulatory properties. Two studies by Liu et al examined lung injury resulting from smoke inhalation. Quercetin was shown to reduce lung injury by lowering the production of inflammatory mediators and free radicals in the lungs of model mice. The effects were more pronounced with extended administration and earlier intervention.^106,107

Seawater Inhalation Lung Injury

Seawater drowning often occurs in situations such as sailing, maritime operations, and naval warfare, and survivors usually suffer ALI induced by seawater inhalation.¹⁰⁸ The innate immune response mediated by lung macrophages plays an essential role in ALI, in which M1-type macrophages can stimulate oxidative damage and inflammatory responses in the lungs by releasing many pro-inflammatory factors and ROS, inducing lung injury.¹⁰⁹ Wang et al conducted a study utilizing a mouse model of seawater inhalation injury, demonstrating that Quercetin significantly decreased iNOS, TNF-α, and IL-1β levels in the lungs. Furthermore, it up-regulated mRNA expression of IL-4 and IL-10, mitigated M1-type macrophage polarization induced by seawater inhalation, reduced inflammatory factors associated with M1-type macrophages, improved arterial blood gases, and lessened interstitial and alveolar hemorrhage as well as structural alterations in lung tissues.¹¹⁰ Therefore, Quercetin may improve gas exchange functions and reduce lung tissue damage caused by seawater inhalation by inhibiting M1-type macrophage polarization and its subsequent immune response.

Quercetin for Treating Hypoxic Lung Injury

The lung is recognized as vulnerable to hypoxia. Hypoxia increases oxidative stress, apoptosis, and inflammation in lung tissue, resulting in pulmonary edema and an increased risk of hypoxic lung injury.¹¹¹ Reducing oxidative stress, inflammation, and apoptosis alleviates hypoxic lung injury. In a rat model of hypoxic lung injury induced by sodium nitrite, Quercetin reduced the expression of immune-inflammatory mediators and heat shock proteins in the lungs. Furthermore, it reduced alveolar wall thickening and inflammatory cell infiltration in the alveolar mesenchyme. When quercetin and melatonin were combined, this protective effect was more evident.¹¹² In another in vivo investigation, quercetin attenuated lung damage brought on by apoptosis by downregulating the expression of Bax protein and up-regulating that of Bcl-2 in rat lungs exposed to hypoxia.¹¹³ According to a study by Ankit Tripathi and associates, quercetin controls the expression of NF-κB and IKα/β that is triggered by hypoxia. This regulation decreased the levels of pro-inflammatory cytokines, such as TNF-α and INF-γ, while simultaneously increasing the levels of anti-inflammatory cytokines within the lungs, such as IL-4 and INF-γ. Furthermore, the study highlighted the role of Quercetin as an activator of Nrf-2, promoting GSH synthesis, enhancing GPX activity, and reducing MDA levels under hypoxic conditions. These effects collectively lowered oxidative stress in the lungs, thereby mitigating hypoxia-induced extravascular leakage and successfully combating hypoxia-induced pulmonary edema in the rat models.¹¹⁴ An in vivo study demonstrated that hypoxia elevated free radical production in the body, leading to oxidative stress and the inhibition of β2-AR signaling. Combining Quercetin and salbutamol reactivated β2-AR signaling under hypoxic conditions, enhancing the lungs’ fluid clearance capacity. This was evidenced by the up-regulation of β2-AR, GPR-1, GPR-10, and GCS-α expression alongside increased lung cAMP content. Furthermore, there was a down-regulation of GRK-2 and NF-κB expression and a reduction in ROS production. It can be concluded that Quercetin can reduce lung inflammation and stimulate β2-AR to enhance AFC in rats, leading to therapeutic and protective effects in hypoxic lung injury.¹¹⁵

Quercetin for Severe Acute Pancreatitis-Associated Lung Injury

Severe acute pancreatitis-associated lung injury (SAP-LI) is one of the most critical complications of pancreatitis, and many of these cases are complicated by ARDS.¹¹⁶ The development of SAP-LI is linked to a syndrome characterized by a systemic inflammatory response resulting from the excessive activation of inflammatory cells in the lungs, delayed apoptosis, and an overproduction of inflammatory mediators.¹¹⁷ Xu et al conducted a study demonstrating that Quercetin mitigates lung injury in SAP model rats by up-regulating Bax expression, down-regulating Bcl-2, enhancing caspase-3 activity, and inducing apoptosis in alveolar neutrophils (PMN).¹¹⁸ Xu’s study demonstrated that Quercetin inhibits the TLR4/NF-κB pathway, effectively blocking the cascade of inflammatory factors while simultaneously inducing apoptosis in alveolar PMNs, thereby mitigating lung injury.⁶⁰

Quercetin Treatment of Lung Injury Caused by Various Types of Pneumonia

Pneumonia is the predominant cause of acute lung damage, and severe pneumonia may advance to ARDS. Bacteria, fungi, and viruses are the predominant agents responsible for pneumonia. Pneumonia-induced ALI mainly involves inflammatory responses in the lungs. Quercetin has anti-inflammatory, antibacterial, and antiviral properties and thus can significantly affect pneumonia. For example, in an in vitro model of Pseudomonas aeruginosa infection of THP-1 macrophages, it was found that quercetin modulated activation of the MAPK pathway and the NLRP3 inflammasome, reducing the release of IL-1β from the cells, and thereby inhibiting the inflammatory response and consequently reducing the invasion of normal cells by pathogens.¹¹⁹ Similar studies found that Quercetin modulated the PI3K/AKT/NF-κB pathway to attenuate Pseudomonas aeruginosa-induced inflammatory responses in the lungs, thereby reducing changes associated with lung damage.¹²⁰ In a mycoplasma-induced chicken pneumonia model, Quercetin regulated the AMPK/SIRT1/NF-κB pathway to suppress the release of inflammatory factors from the lungs, thus reducing inflammatory lung injury.¹²¹ In a distinct study, Quercetin inhibited pneumococcal hemolysin (PLY) activity, thereby effectively obstructing pneumonia induced by Streptococcus pneumoniae. In in vitro experiments, quercetin treatment reduced PLY activity, consequently protecting alveolar epithelial cells from PLY-induced damage and enhancing cell survival. In vivo studies further showed that Quercetin reduced the dry-to-wet weight ratio of lung tissue, suppressed the release of inflammatory factors (IL-1β, TNF-α) in the BALF, and alleviated lung tissue edema, offering comprehensive defense against Streptococcus pneumoniae infection.¹²² Network-based pharmacological and metabolomic investigations have demonstrated that Quercetin mitigates inflammatory lung injury induced by a respiratory syncytial virus (RSV) primarily by restoring mice metabolism changes resulting from RSV infection.¹²³ A study by Guimaraes’ team demonstrated that the M2-1 protein of RSV, functioning as an anti-termination factor during transcription, is crucial in the premature dissociation of polymers, indicating its potential as a target for inhibitors of viral replication. This research synthesized quercetin tetraacetate and quercetin pentaacetate, acetylated quercetin derivatives, which interacted with the M2-1 RNA-binding site to inhibit viral replication. The findings highlight their potential therapeutic advantages in treating respiratory conditions, including pneumonia and bronchitis.¹²⁴

Severe Acute Respiratory Syndrome SARS-CoV-2 was the virus responsible for COVID-19, a new coronavirus-associated pneumonia. COVID-19 was associated with the onset of concurrent ALI/ARDS and imposed a significant strain on the global economy and healthcare from its initial outbreak in 2019 and subsequent proliferation; a specific therapy for COVID-19 remains unknown.^125,126 Therefore, extensive research has been undertaken on the application of herbal medicine for the treatment of COVID-19; for instance, China and South Korea have established guidelines for the prevention and management of SARS-CoV-2 infections employing traditional medicines, with Quercetin identified as a potential therapeutic agent owing to its diverse bioactivities and pharmacological effects.^127,128 A clinical trial demonstrated that Quercetin is effective in treating SARS-CoV-2 infection.¹²⁹ A clinical prospective study has shown the reliability of Quercetin in alleviating early symptoms and preventing progression to severe COVID-19.¹³⁰ The hydroxyl groups of Quercetin inhibit 85% of SARS-CoV 3CLpro expression by binding to the Gln189 site on 3CLpro, thereby preventing hydrolysis and blocking viral proliferation.^131–133 During viral infection, Quercetin was found to inhibit the virus-induced release of inflammatory factors, chemokines, and growth factors in macrophages via the calcium-STAT pathway, thereby attenuating virally induced inflammatory responses in the lungs and consequently mitigating lung injury.¹³⁴ Quercetin is also known for its extremely low cytotoxicity and can thus be used to prevent SARS-CoV invasion of host cells.¹³⁵ A review of Quercetin indicates that its combination with vitamin C demonstrates antiviral and immunomodulatory effects, enhancing therapeutic outcomes for COVID-19 and mitigating lung injury.¹³⁶ The results suggest that Quercetin may be an effective treatment for COVID-19.

Nano-Formulations of Quercetin for the Treatment of Acute Lung Injury

Numerous studies have shown that quercetin has a protective effect against numerous diseases. However, quercetin also has certain limitations in clinical applications, such as poor water solubility (< 7 μg/mL), low bioavailability (1–2%), high metabolic rate, poor absorption, and susceptibility to acidic environments¹³⁷ which have limited its use to the point where it has not yet been approved for clinical use. Thus, the finding of quercetin carriers is crucial. Currently, the hottest research is on nano-formulations, which can alter the solubility efficiency and improve the bioavailability of quercetin. Nano-formulations of quercetin include nanocrystals, nanoliposomes, polymeric micelles, nanocapsules, nano-emulsions, and nanoparticles (Figure 2).¹³⁸ Compared to conventional drugs, nano-formulations decrease particle size, enhance the absorption area, and improve solubility, thereby modifying pharmacokinetics and tissue distribution and increasing drug bioavailability.¹³⁸ Numerous studies indicate that quercetin nanoparticles exhibit protective effects on the cardiovascular,¹³⁹ digestive,¹⁴⁰ urinary,¹⁴¹ nervous,¹⁴² and respiratory systems¹⁴³ and demonstrate antitumor³³ and anti-allergy properties.¹⁴⁴

Figure 2 Classification of quercetin nano-formulations.

Patients with ALI/ARDS often suffer from poor metabolism, malabsorption, and disorders of the gastrointestinal environment, so there is a need to develop drugs that can be easily absorbed, and, although quercetin has a significant therapeutic effect on ALI, its low bioavailability limits its utilization. To address this problem, Chen et al developed an inhalable alginate quercetin nanogel (QU-Nanogel) based on alginate which is an FDA-approved polysaccharide with good biocompatibility. The QU-Nanogel had a uniform particle size distribution of less than 100 nm, facilitating the exposure of the active site on the surface, making it more readily absorbed and thus increasing the bioavailability of quercetin. It was also found that inhalation of the QU-Nanogel in model rats could reverse damage caused by oxidative stress and down-regulate the expression of inflammatory factors associated with ALI, reducing lung inflammation and preventing pulmonary fibrosis, thus mitigating lung injury¹⁴⁴ In addition, Liu et al found that quercetin liposomes could reduce radiation-induced oxidative stress in the lungs, alleviate acute pneumonitis, and delay the emergence of advanced fibrosis, thus effectively protecting mouse lung tissues from attack by the Lepidoderma slime mold.⁸² Therefore, if quercetin is used in clinical applications, the use of quercetin nano-formulations would be preferred. Although quercetin nanoformulations have been found to be effective against ALI, the number of investigations is limited and research investment in this field needs to be strengthened.

Summary and Outlook

With a high safety profile and minimal side effects, quercetin is a naturally occurring flavonoid that is extensively distributed in nature and exhibits a variety of biological activities and pharmacological effects. In ALI cases, it can suppress oxidative stress, inflammatory reactions, cell death, apoptosis, fibrosis, and bacterial and viral infections by targeting various pathways and signaling processes. This versatility indicates its potential to mitigate the different forms of ALI. This study presents a systematic classification of ALI based on existing research findings.

Quercetin has demonstrated encouraging therapeutic effects on acute lung damage and other conditions. Quercetin protects the neurological system and can improve the prognosis and clinical symptoms of neurodegenerative disorders, stroke, Parkinson’s disease, and Alzheimer’s disease.^86,145 Quercetin mitigates cardiovascular diseases by regulating blood pressure, inhibiting ventricular remodeling, improving cardiac function, and protecting against myocardial damage caused by diabetes and hyperthyroidism.^146,147 It also exhibits antiarrhythmic properties and potential therapeutic effects in infective endocarditis.¹⁴⁸ Quercetin has a therapeutic effect on acute kidney injury caused by various reasons and shows potential as an anti-kidney injury agent.¹⁴⁹ It also displays a hepatoprotective effect by reducing bile acid reabsorption, inhibiting the NTCP transporter expression, and controlling hepatic lipid metabolism.^150,151 Quercetin acts as an antitumor agent by preventing tumor cell proliferation, migration, invasion, and other mechanisms. It also improves the effects of some chemotherapeutic drugs, reduces multidrug resistance, and improves patient quality of life.^152,153 The therapeutic applications of Quercetin for various disorders have been briefly discussed above; different diseases could benefit from quercetin in both research and practical applications, highlighting its broad therapeutic potential. Therefore, Quercetin is a very promising therapeutic candidate molecule for drug development.

Despite the evident therapeutic effects of Quercetin on ALI, this review presents several limitations. The current research on Quercetin for treating ALI reveals two important shortcomings in the discussion. The current research on applying Quercetin in the treatment of ALI lacks comprehensiveness. Topics such as lung injuries induced by trauma, drugs, transfusion, mechanical ventilation, thermal radiation, phosgene inhalation, gastric contents inhalation, acute organophosphorus poisoning, meconium inhalation, and dust inhalation have not been addressed. There are no relevant reports on these clinically prevalent forms of ALI. Further research on the application of quercetin in various types of lung injury is essential to enhance the accessibility of its treatment.Several experimental cases assessing quercetin’s efficacy in treating ALI can be broadened by conducting studies that incorporate quercetin interventions informed by newly identified mechanisms associated with ALI. In investigating fundamental concepts and mechanisms, it is crucial to consider the relationships and functions of each mechanism. Limitations in experimental conditions, expertise, and financial resources render a complete understanding of all relevant mechanisms of action impractical, thereby necessitating comprehensive review articles to synthesize the findings. The second limitation is that most studies investigating Quercetin’s efficacy in treating ALI have predominantly focused on basic experimental approaches. The lack of clinical trials necessitates the incorporation of findings from basic research to investigate the clinical effectiveness of this treatment further. Thirdly, Quercetin may cause several side effects. Users have reported experiencing nausea, vomiting, diarrhea, abdominal pain, headaches, and a tingling sensation in the limbs, along with other discomforts. In some cases, severe complications such as acute hepatic and renal insufficiency can occur. Additionally, when quercetin is taken with medications that are metabolized by the cytochrome P450 enzyme, the likelihood of side effects increases significantly.¹⁵⁴ Research on the adverse side effects of Quercetin is limited, and it remains unclear whether other deleterious consequences exist. Therefore, researchers should focus on the side effects of Quercetin to alleviate potential risks in future studies on Quercetin and lung injury.

Quercetin has been extensively studied in the medical field due to its well-established therapeutic mechanisms, high safety profile, and minimal side effects. However, its low bioavailability remains a significant barrier to the advancement of Quercetin as a therapeutic agent. This issue necessitates solutions involving drug delivery carriers, developing quercetin precursors, and synthesizing quercetin analogs and derivatives, among other approaches. Despite the existing research, the advancement of Quercetin into clinical applications remains a significant challenge.