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Previous studies have implicated persistent innate immune signaling in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a familial non-ischemic heart muscle disease characterized by life-threatening arrhythmias and progressive myocardial injury. Here, we provide new evidence implicating inflammatory lipid autocoids in ACM. We show that specialized pro-resolving lipid mediators are reduced in hearts of Dsg2mut/mut mice, a well characterized mouse model of ACM. We also found that ACM disease features can be reversed in rat ventricular myocytes expressing mutant JUP by the pro-resolving epoxy fatty acid (EpFA) 14,15-eicosatrienoic acid (14-15-EET), whereas 14,15-EE-5(Z)E which antagonizes actions of the putative 14,15-EET receptor, intensified nuclear accumulation of the desmosomal protein plakoglobin. Soluble epoxide hydrolase (sEH), an enzyme that rapidly converts pro-resolving EpFAs into polar, far less active or even pro-inflammatory diols, is highly expressed in cardiac myocytes in Dsg2mut/mut mice. Inhibition of sEH prevented progression of myocardial injury in Dsg2mut/mut mice and led to recovery of contractile function. This was associated with reduced myocardial expression of genes involved in the innate immune response and fewer pro-inflammatory macrophages expressing CCR2, which mediate myocardial injury in Dsg2mut/mut mice. These results suggest that pro-inflammatory eicosanoids contribute to the pathogenesis of ACM and, further, that inhibition of sEH may be an effective, mechanism-based therapy for ACM patients.
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Cancer therapy, including immunotherapy, is inherently limited by chronic inflammation-induced tumorigenesis and toxicity within the tumor microenvironment. Thus, stimulating the resolution of inflammation may enhance immunotherapy and improve the toxicity of immune checkpoint inhibition (ICI). As epoxy-fatty acids (EpFAs) are degraded by the enzyme soluble epoxide hydrolase (sEH), the inhibition of sEH increases endogenous EpFA levels to promote the resolution of cancer-associated inflammation. Here, we demonstrate that systemic treatment with ICI induces sEH expression in multiple murine cancer models. Dietary omega-3 polyunsaturated fatty acid supplementation and pharmacologic sEH inhibition, both alone and in combination, significantly enhance anti-tumor activity of ICI in these models. Notably, pharmacological abrogation of the sEH pathway alone or in combination with ICI counter-regulates an ICI-induced pro-inflammatory and pro-tumorigenic cytokine storm. Thus, modulating endogenous EpFA levels through dietary supplementation or sEH inhibition may represent a unique strategy to enhance the anti-tumor activity of paradigm cancer therapies.
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Epóxido Hidrolases , Neoplasias , Camundongos , Humanos , Animais , Epóxido Hidrolases/metabolismo , Ácidos Graxos/metabolismo , Inflamação/metabolismo , Neoplasias/terapia , Imunoterapia , Microambiente TumoralRESUMO
While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small-molecule antagonists of single EP receptors, the cyclooxygenase-2 (COX-2) inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous, and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8+ T cells in vitro as compared with single EP antagonists. CD8+ T-cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased tumor microenvironment lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC)min+/- spontaneous colorectal tumor model, compared with celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small-molecule dual EP2/EP4 antagonist. Significance: Prostaglandin (PGE2) drives tumor progression but the pathway has not been effectively drugged. We demonstrate significantly enhanced immunologic potency and antitumor activity through blockade of EP2 and EP4 PGE2 receptor signaling together with a single molecule.
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Neoplasias , Prostaglandinas , Humanos , Animais , Camundongos , Dinoprostona/metabolismo , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Celecoxib/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Inibidores de Ciclo-Oxigenase 2 , Microambiente TumoralRESUMO
BACKGROUND: Cancer is a major burden of disease worldwide and increasing evidence shows that inflammation contributes to cancer development and progression. Eicosanoids are derived from dietary polyunsaturated fatty acids, such as arachidonic acid (AA), and are mainly produced by a series of enzymatic pathways that include cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 epoxygenase (CYP). Eicosanoids consist of at least several hundred individual molecules and play important roles in the inflammatory response and inflammation-related cancers. SCOPE AND APPROACH: Dietary sources of AA and biosynthesis of eicosanoids from AA through different metabolic pathways are summarized. The bioactivities of eicosanoids and their potential molecular mechanisms on inflammation and cancer are revealed. Additionally, current challenges and limitations in eicosanoid research on inflammation-related cancer are discussed. KEY FINDINGS AND CONCLUSIONS: Dietary AA generates a large variety of eicosanoids, including prostaglandins, thromboxane A2, leukotrienes, cysteinyl leukotrienes, lipoxins, hydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatrienoic acids (EETs). Eicosanoids exert different bioactivities and mechanisms involved in the inflammation and related cancer developments. A deeper understanding of eicosanoid biology may be advantageous in cancer treatment and help to define cellular targets for further therapeutic development.
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Eicosanoides , Neoplasias , Humanos , Eicosanoides/metabolismo , Ácido Araquidônico/metabolismo , Neoplasias/metabolismo , Leucotrienos , Inflamação/metabolismo , Ciclo-Oxigenase 2RESUMO
Aflatoxin B1 (AFB1) contamination in food and feed leads to severe global health problems. Acting as the frontier immunological barrier, the intestinal mucosa is constantly challenged by exposure to foodborne toxins such as AFB1 via contaminated diets, but the detailed toxic mechanism and endogenous regulators of AFB1 toxicity are still unclear. Here, we showed that AFB1 disrupted intestinal immune function by suppressing macrophages, especially M2 macrophages, and antimicrobial peptide-secreting Paneth cells. Using an oxylipinomics approach, we identified that AFB1 immunotoxicity is associated with decreased epoxy fatty acids, notably epoxyeicosatrienoic acids, and increased soluble epoxide hydrolase (sEH) levels in the intestine. Furthermore, sEH deficiency or inhibition rescued the AFB1-compromised intestinal immunity by restoring M2 macrophages as well as Paneth cells and their-derived lysozyme and α-defensin-3 in mice. Altogether, our study demonstrates that AFB1 exposure impairs intestinal immunity, at least in part, in a sEH-mediated way. Moreover, the present study supports the potential application of pharmacological intervention by inhibiting the sEH enzyme in alleviating intestinal immunotoxicity and associated complications caused by AFB1 global contamination.
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Aflatoxina B1 , Epóxido Hidrolases , Animais , Camundongos , Aflatoxina B1/toxicidade , Dieta , Imunidade , IntestinosRESUMO
Angiogenesis, the growth of new blood vessels, plays a critical role in tissue repair and regeneration, as well as in cancer. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving mediators (SPMs), including resolvins. Angiogenesis and the resolution of inflammation are critical interdependent processes. Disrupted inflammation resolution can accelerate tumor growth, which is angiogenesis-dependent. SPMs, including resolvins and lipoxins, inhibit physiologic and pathological angiogenesis at nanogram concentrations. The failure of resolution of inflammation is an emerging hallmark of angiogenesis-dependent diseases including arthritis, psoriasis, diabetic retinopathy, age-related macular degeneration, inflammatory bowel disease, atherosclerosis, endometriosis, Alzheimer's disease, and cancer. Whereas therapeutic angiogenesis repairs tissue damage (e.g., limb ischemia), inhibition of pathological angiogenesis suppresses tumor growth and other non-neoplastic diseases such as retinopathies. Stimulation of resolution of inflammation via pro-resolving lipid mediators promotes the repair of tissue damage and wound healing, accelerates tissue regeneration, and inhibits cancer. Here we provide an overview of the mechanisms of cross talk between angiogenesis and inflammation resolution in chronic inflammation-driven diseases. Stimulating the resolution of inflammation via pro-resolving lipid mediators has emerged as a promising new field to treat angiogenic diseases.
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Aterosclerose , Inflamação , Humanos , Inflamação/patologia , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Isquemia , Lipídeos , Neovascularização Patológica , Mediadores da Inflamação/uso terapêuticoRESUMO
Pancreatic ductal adenocarcinoma (PDA) is an aggressive metastatic cancer with a very low survival rate. This tumor is hypovascularized and characterized by severe hypoxic regions, yet these regions are not impeded by the oxidative stress in their microenvironment. PDA's high resilience raises the need to find new effective therapeutic targets. This study investigated the suitability of methionine aminopeptidase 2 (MetAp2), a metallopeptidase known to play an important role in tumor progression, as a new target for treating PDA. In our examination of patient-derived PDA tissues, we found that MetAp2 is highly expressed in metastatic regions compared with primary sites. At the cellular level, we found that the basal expression levels of MetAp2 in pancreatic cancer cells were higher than its levels in endothelial cells. Pancreatic cancer cells showed a significant suppression of proliferation in a dose-dependent manner upon exposure to TNP-470, a selective MetAp2 inhibitor. In addition, a significant reduction in glutathione (GSH) levels - known for its importance in alleviating oxidative stress - was detected in all treated cells, suggesting a possible anti-cancer activity mechanism that would be feasible for treating highly hypoxic PDA tumors. Furthermore, in an orthotopic pancreatic cancer murine model, systemic oral treatment with a MetAp2 inhibitor significantly reduced tumors' growth. Taken together, our findings indicate that MetAp2 enhances tumor sensitivity to hypoxia and may provide an effective target for treating hypoxic tumors with high expression levels of MetAp2.
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Mycobacterium tuberculosis (Mtb) is the pathogen that causes tuberculosis (TB), a leading infectious disease of humans worldwide. One of the main histopathological hallmarks of TB is the formation of granulomas comprised of elaborately organized aggregates of immune cells containing the pathogen. Dissemination of Mtb from infected cells in the granulomas due to host and mycobacterial factors induces multiple cell death modalities in infected cells. Based on molecular mechanism, morphological characteristics, and signal dependency, there are two main categories of cell death: programmed and nonprogrammed. Programmed cell death (PCD), such as apoptosis and autophagy, is associated with a protective response to Mtb by keeping the bacteria encased within dead macrophages that can be readily phagocytosed by arriving in uninfected or neighboring cells. In contrast, non-PCD necrotic cell death favors the pathogen, resulting in bacterial release into the extracellular environment. Multiple types of cell death in the PCD category, including pyroptosis, necroptosis, ferroptosis, ETosis, parthanatos, and PANoptosis, may be involved in Mtb infection. Since PCD pathways are essential for host immunity to Mtb, therapeutic compounds targeting cell death signaling pathways have been experimentally tested for TB treatment. This review summarizes different modalities of Mtb-mediated host cell deaths, the molecular mechanisms underpinning host cell death during Mtb infection, and its potential implications for host immunity. In addition, targeting host cell death pathways as potential therapeutic and preventive approaches against Mtb infection is also discussed.
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Mycobacterium tuberculosis , Tuberculose , Humanos , Tuberculose/microbiologia , Tuberculose/prevenção & controle , Mycobacterium tuberculosis/metabolismo , Morte Celular , Macrófagos/metabolismo , Granuloma/metabolismo , Granuloma/microbiologia , Granuloma/patologia , Interações Hospedeiro-PatógenoRESUMO
Glioblastoma is the most malignant form of glioma, which is the most commonly occurring tumor of the central nervous system. Notch signaling in glioblastoma is considered to be a marker of an undifferentiated tumor cell state, associated with tumor stem cells. Notch is also known for facilitating tumor dormancy escape, recurrence and progression after treatment. Studies in vitro suggest that reducing, removing or blocking the expression of this gene triggers tumor cell differentiation, which shifts the phenotype away from stemness status and consequently facilitates treatment. In contrast, in the vasculature, Notch appears to also function as an important receptor that defines mature non-leaking vessels, and increasing its expression promotes tumor normalization in models of cancer in vivo. Failures in clinical trials with Notch inhibitors are potentially related to their opposing effects on the tumor versus the tumor vasculature, which points to the need for a greater understanding of this signaling pathway.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Glioblastoma/genética , Glioma/patologia , Humanos , Células-Tronco Neoplásicas/patologia , Transdução de SinaisRESUMO
Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been an ongoing pandemic causing significant morbidity and mortality worldwide. The "cytokine storm" is a critical driving force in severe COVID-19 cases, leading to hyperinflammation, multi-system organ failure, and death. A paradigm shift is emerging in our understanding of the resolution of inflammation from a passive course to an active biochemical process driven by endogenous specialized pro-resolving mediators (SPMs), such as resolvins, protectins, lipoxins, and maresins. SPMs stimulate macrophage-mediated debris clearance and counter pro-inflammatory cytokine production, a process collectively termed as the "resolution of inflammation." Hyperinflammation is not unique to COVID-19 and also occurs in neoplastic conditions, putting individuals with underlying health conditions such as cancer at elevated risk of severe SARS-CoV-2 infection. Despite approaches to block systemic inflammation, there are no current therapies designed to stimulate the resolution of inflammation in patients with COVID-19 or cancer. A non-immunosuppressive therapeutic approach that reduces the cytokine storm in patients with COVID-19 and cancer is urgently needed. SPMs are potent immunoresolvent and organ-protective lipid autacoids that stimulate the resolution of inflammation, facilitate clearance of infections, reduce thrombus burden, and promote a return to tissue homeostasis. Targeting endogenous lipid mediators, such as SPMs, offers an entirely novel approach to control SARS-CoV-2 infection and cancer by increasing the body's natural reserve of pro-resolving mediators without overt toxicity or immunosuppression.
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COVID-19 , Neoplasias , Síndrome da Liberação de Citocina/etiologia , Humanos , Inflamação , Pandemias , SARS-CoV-2RESUMO
Current cancer therapies aim at eradicating cancer cells from the body. However, killing cells generates cell "debris" which can promote tumor progression. Thus, therapy can be a double-edged sword. Specifically, injury and debris generated by cancer therapies, including chemotherapy, radiation, and surgery, may offset their benefit by promoting the secretion of pro-tumorigenic factors (e.g., eicosanoid-driven cytokines) that stimulate regrowth and metastasis of surviving cells. The debris produced by cytotoxic cancer therapy can also contribute to a tumor microenvironment that promotes tumor progression and recurrence. Although not well understood, several molecular mechanisms have been implicated in debris-stimulated tumor growth that we review here, such as the involvement of extracellular vesicles, exosomal miR-194-5p, Bax, Bak, Smac, HMGB1, cytokines, and caspase-3. We discuss the cases of pancreatic and other cancer types where debris promotes postoperative tumor recurrence and metastasis, thus offering a new opportunity to prevent cancer progression intrinsically linked to treatment by stimulating resolution of tumor-promoting debris.
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Antineoplásicos , MicroRNAs , Neoplasias , Linhagem Celular Tumoral , Citocinas , Eicosanoides , Humanos , Neoplasias/terapia , Microambiente TumoralRESUMO
Cancer therapy reduces tumor burden via tumor cell death ("debris"), which can accelerate tumor progression via the failure of inflammation resolution. Thus, there is an urgent need to develop treatment modalities that stimulate the clearance or resolution of inflammation-associated debris. Here, we demonstrate that chemotherapy-generated debris stimulates metastasis by up-regulating soluble epoxide hydrolase (sEH) and the prostaglandin E2 receptor 4 (EP4). Therapy-induced tumor cell debris triggers a storm of proinflammatory and proangiogenic eicosanoid-driven cytokines. Thus, targeting a single eicosanoid or cytokine is unlikely to prevent chemotherapy-induced metastasis. Pharmacological abrogation of both sEH and EP4 eicosanoid pathways prevents hepato-pancreatic tumor growth and liver metastasis by promoting macrophage phagocytosis of debris and counterregulating a protumorigenic eicosanoid and cytokine storm. Therefore, stimulating the clearance of tumor cell debris via combined sEH and EP4 inhibition is an approach to prevent debris-stimulated metastasis and tumor growth.
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Eicosanoides/metabolismo , Epóxido Hidrolases/biossíntese , Macrófagos/imunologia , Metástase Neoplásica/patologia , Receptores de Prostaglandina E Subtipo EP4/biossíntese , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica/prevenção & controle , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Fagocitose/imunologia , Células RAW 264.7RESUMO
The resolution of inflammation has emerged as a critical endogenous process that protects host tissues from prolonged or excessive inflammation that can become chronic. Failure of the resolution of inflammation is a key pathological mechanism that drives the progression of numerous inflammation-driven diseases. Essential polyunsaturated fatty acid (PUFA)-derived autacoid mediators termed 'specialized pro-resolving mediators' (SPMs) regulate endogenous resolution programs by limiting further neutrophil tissue infiltration and stimulating local immune cell (e.g., macrophage)-mediated clearance of apoptotic polymorphonuclear neutrophils, cellular debris, and microbes, as well as counter-regulating eicosanoid/cytokine production. The SPM superfamily encompasses lipoxins, resolvins, protectins, and maresins. Our understanding of the resolution phase of acute inflammation has grown exponentially in the past three decades with the discovery of novel pro-resolving lipid mediators, their pro-efferocytosis mechanisms, and their receptors. Technological advancement has further facilitated lipid mediator metabolipidomic based profiling of healthy and diseased human tissues, highlighting the extraordinary therapeutic potential of SPMs across a broad array of inflammatory diseases including cancer. As current front-line cancer therapies such as surgery, chemotherapy, and radiation may induce various unwanted side effects such as robust pro-inflammatory and pro-tumorigenic host responses, characterizing SPMs and their receptors as novel therapeutic targets may have important implications as a new direction for host-targeted cancer therapy. Here, we discuss the origins of inflammation resolution, key discoveries and the failure of resolution mechanisms in diseases with an emphasis on cancer, and future directions focused on novel therapeutic applications for this exciting and rapidly expanding field.
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Inflamação , Biologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , MedicinaRESUMO
Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to induce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macrophage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation, including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors, may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans.
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Carcinogênese , Inflamação , Carcinógenos/toxicidade , Eicosanoides , Humanos , Inflamação/patologia , Mediadores da Inflamação , Neoplasias/induzido quimicamente , Neoplasias/tratamento farmacológico , Microambiente TumoralRESUMO
Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on days 1 and 14. In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis.
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Injúria Renal Aguda/tratamento farmacológico , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glomerulonefrite/prevenção & controle , Hipertensão/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/fisiopatologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/toxicidade , Modelos Animais de Doenças , Progressão da Doença , Enalapril/farmacologia , Inibidores Enzimáticos/toxicidade , Epóxido Hidrolases/antagonistas & inibidores , Fibrose , Mesângio Glomerular/efeitos dos fármacos , Mesângio Glomerular/patologia , Mesângio Glomerular/fisiopatologia , Glomerulonefrite/etiologia , Glomerulonefrite/patologia , Glomerulonefrite/fisiopatologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Masculino , Camundongos , Compostos de Fenilureia/toxicidade , Piperidinas/toxicidade , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/fisiopatologiaRESUMO
Toxic environmental carcinogens promote cancer via genotoxic and nongenotoxic pathways, but nongenetic mechanisms remain poorly characterized. Carcinogen-induced apoptosis may trigger escape from dormancy of microtumors by interfering with inflammation resolution and triggering an endoplasmic reticulum (ER) stress response. While eicosanoid and cytokine storms are well-characterized in infection and inflammation, they are poorly characterized in cancer. Here, we demonstrate that carcinogens, such as aflatoxin B1 (AFB1), induce apoptotic cell death and the resulting cell debris stimulates hepatocellular carcinoma (HCC) tumor growth via an "eicosanoid and cytokine storm." AFB1-generated debris up-regulates cyclooxygenase-2 (COX-2), soluble epoxide hydrolase (sEH), ER stress-response genes including BiP, CHOP, and PDI in macrophages. Thus, selective cytokine or eicosanoid blockade is unlikely to prevent carcinogen-induced cancer progression. Pharmacological abrogation of both the COX-2 and sEH pathways by PTUPB prevented the debris-stimulated eicosanoid and cytokine storm, down-regulated ER stress genes, and promoted macrophage phagocytosis of debris, resulting in suppression of HCC tumor growth. Thus, inflammation resolution via dual COX-2/sEH inhibition is an approach to prevent carcinogen-induced cancer.
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Citocinas/metabolismo , Eicosanoides/metabolismo , Neoplasias Hepáticas/metabolismo , Aflatoxina B1/efeitos adversos , Animais , Apoptose , Carcinogênese/metabolismo , Carcinógenos/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Citocinas/imunologia , Progressão da Doença , Eicosanoides/imunologia , Epóxido Hidrolases/metabolismo , Células Hep G2 , Humanos , Inflamação/metabolismo , Neoplasias Hepáticas/fisiopatologia , Macrófagos/metabolismo , Camundongos , Processos NeoplásicosRESUMO
Severe coronavirus disease 2019 (COVID-19) symptoms, including systemic inflammatory response and multisystem organ failure, are now affecting thousands of infected patients and causing widespread mortality. Coronavirus infection causes tissue damage, which triggers the endoplasmic reticulum stress response and subsequent eicosanoid and cytokine storms. Although proinflammatory eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, are critical mediators of physiological processes, such as inflammation, fever, allergy, and pain, their roles in COVID-19 are poorly characterized. Arachidonic acid-derived epoxyeicosatrienoic acids could alleviate the systemic hyperinflammatory response in COVID-19 infection by modulating endoplasmic reticulum stress and stimulating the resolution of inflammation. Soluble epoxide hydrolase (sEH) inhibitors, which increase endogenous epoxyeicosatrienoic acid levels, exhibit potent anti-inflammatory activity and inhibit various pathologic processes in preclinical disease models, including pulmonary fibrosis, thrombosis, and acute respiratory distress syndrome. Therefore, targeting eicosanoids and sEH could be a novel therapeutic approach in combating COVID-19. In this review, we discuss the predominant role of eicosanoids in regulating the inflammatory cascade and propose the potential application of sEH inhibitors in alleviating COVID-19 symptoms. The host-protective action of omega-3 fatty acid-derived epoxyeicosanoids and specialized proresolving mediators in regulating anti-inflammation and antiviral response is also discussed. Future studies determining the eicosanoid profile in COVID-19 patients or preclinical models are pivotal in providing novel insights into coronavirus-host interaction and inflammation modulation.
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Anti-Inflamatórios/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Animais , Betacoronavirus/patogenicidade , COVID-19 , Eicosanoides/farmacologia , Eicosanoides/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Pandemias , SARS-CoV-2RESUMO
Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation and potentially life-threatening "cytokine storms". Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death ("debris")-induced "eicosanoid storm", including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophage-mediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on "anti-viral" and "anti-inflammatory" strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.