-
Cell Reports Aug 2023Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has...
Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine primes innate immune signaling to exacerbate systemic inflammation during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma 3-hydroxykynurenine levels that prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes with interleukin-1β to cause cellular apoptosis. Critically, mice with elevated 3-hydroxykynurenine succumb fatally earlier and more readily to experimental AP. Therapeutically, blockade with the highly selective KMO inhibitor GSK898 rescues the phenotype, reducing 3-hydroxykynurenine and protecting against critical illness and death. Together, our findings establish KMO and 3-hydroxykynurenine as regulators of inflammation and the innate immune response to sterile inflammation. During critical illness, excess morbidity and death from multiple organ failure can be rescued by systemic KMO blockade.
Topics: Mice; Animals; Kynurenine; Pancreatitis; Critical Illness; Multiple Organ Failure; Acute Disease; Mice, Knockout; Inflammation; Kynurenine 3-Monooxygenase
PubMed: 37478012
DOI: 10.1016/j.celrep.2023.112763 -
Frontiers in Public Health 2023Long COVID is a clinical entity characterized by persistent health problems or development of new diseases, without an alternative diagnosis, following SARS-CoV-2...
BACKGROUND
Long COVID is a clinical entity characterized by persistent health problems or development of new diseases, without an alternative diagnosis, following SARS-CoV-2 infection that affects a significant proportion of individuals globally. It can manifest with a wide range of symptoms due to dysfunction of multiple organ systems including but not limited to cardiovascular, hematologic, neurological, gastrointestinal, and renal organs, revealed by observational studies. However, a causal association between the genetic predisposition to COVID-19 and many post-infective abnormalities in long COVID remain unclear.
METHODS
Here we employed Mendelian randomization (MR), a robust genetic epidemiological approach, to investigate the potential causal associations between genetic predisposition to COVID-19 and long COVID symptoms, namely pulmonary (pneumonia and airway infections including bronchitis, emphysema, asthma, and rhinitis), neurological (headache, depression, and Parkinson's disease), cardiac (heart failure and chest pain) diseases, and chronic fatigue. Using two-sample MR, we leveraged genetic data from a large COVID-19 genome-wide association study and various disorder-specific datasets.
RESULTS
This analysis revealed that a genetic predisposition to COVID-19 was significantly causally linked to an increased risk of developing pneumonia, airway infections, headache, and heart failure. It also showed a strong positive correlation with chronic fatigue, a frequently observed symptom in long COVID patients. However, our findings on Parkinson's disease, depression, and chest pain were inconclusive.
CONCLUSION
Overall, these findings provide valuable insights into the genetic underpinnings of long COVID and its diverse range of symptoms. Understanding these causal associations may aid in better management and treatment of long COVID patients, thereby alleviating the substantial burden it poses on global health and socioeconomic systems.
Topics: Humans; Post-Acute COVID-19 Syndrome; COVID-19; Fatigue Syndrome, Chronic; Genome-Wide Association Study; Mendelian Randomization Analysis; Parkinson Disease; SARS-CoV-2; Heart Failure; Chest Pain; Genetic Predisposition to Disease; Headache
PubMed: 38155884
DOI: 10.3389/fpubh.2023.1303183 -
Physiological Reviews Apr 2024Lung endothelia in the arteries, capillaries, and veins are heterogeneous in structure and function. Lung capillaries in particular represent a unique vascular niche,... (Review)
Review
Lung endothelia in the arteries, capillaries, and veins are heterogeneous in structure and function. Lung capillaries in particular represent a unique vascular niche, with a thin yet highly restrictive alveolar-capillary barrier that optimizes gas exchange. Capillary endothelium surveys the blood while simultaneously interpreting cues initiated within the alveolus and communicated via immediately adjacent type I and type II epithelial cells, fibroblasts, and pericytes. This cell-cell communication is necessary to coordinate the immune response to lower respiratory tract infection. Recent discoveries identify an important role for the microtubule-associated protein tau that is expressed in lung capillary endothelia in the host-pathogen interaction. This endothelial tau stabilizes microtubules necessary for barrier integrity, yet infection drives production of cytotoxic tau variants that are released into the airways and circulation, where they contribute to end-organ dysfunction. Similarly, beta-amyloid is produced during infection. Beta-amyloid has antimicrobial activity, but during infection it can acquire cytotoxic activity that is deleterious to the host. The production and function of these cytotoxic tau and amyloid variants are the subject of this review. Lung-derived cytotoxic tau and amyloid variants are a recently discovered mechanism of end-organ dysfunction, including neurocognitive dysfunction, during and in the aftermath of infection.
Topics: Humans; Multiple Organ Failure; Lung; Endothelium, Vascular; Amyloid; Amyloid beta-Peptides
PubMed: 37561137
DOI: 10.1152/physrev.00006.2023 -
Heliyon Aug 2023Ebola virus disease (EVD) is a severe and highly fatal zoonotic disease caused by viruses in the family and genus . The disease first appeared in Zaire near the Ebola... (Review)
Review
Ebola virus disease (EVD) is a severe and highly fatal zoonotic disease caused by viruses in the family and genus . The disease first appeared in Zaire near the Ebola River in 1976, now in the Democratic Republic of the Congo. Since then, several outbreaks have been reported in different parts of the world, mainly in Africa, leading to the identification of six distinct viral strains that cause disease in humans and other primates. Bats are assumed to be the main reservoir hosts of the virus, and the initial incidence of human epidemics invariably follows exposure to infected forest animals through contact or consumption of bush meat and body fluids of forest animals harboring the disease. Human-to-human transmission occurs when contaminated body fluids, utensils, and equipment come in contact with broken or abraded skin and mucous membranes. EVD is characterized by sudden onset of 'flu-like' symptoms (fever, myalgia, chills), vomiting and diarrhea, then disease rapidly evolves into a severe state with a rapid clinical decline which may lead potential hemorrhagic complications and multiple organ failure. Effective EVD prevention, detection, and response necessitate strong coordination across the animal, human, and environmental health sectors, as well as well-defined roles and responsibilities evidencing the significance of one health approach; the natural history, epidemiology, pathogenesis, and diagnostic procedures of the Ebola virus, as well as prevention and control efforts in light of one health approach, are discussed in this article.
PubMed: 37600424
DOI: 10.1016/j.heliyon.2023.e19036 -
Fa Yi Xue Za Zhi Dec 2023The coronavirus disease 2019 (COVID-19) has been a global epidemic for more than three years, causing more than 6.9 million deaths. COVID-19 has the clinical... (Review)
Review
The coronavirus disease 2019 (COVID-19) has been a global epidemic for more than three years, causing more than 6.9 million deaths. COVID-19 has the clinical characteristics of strong infectivity and long incubation period, and can cause multi-system damage, mainly lung damage, clinical symptoms of acute respiratory distress syndrome (ARDS) and systemic multiple organ damage. The SARS-CoV-2 virus is still constantly mutating. At present, there is no global consensus on the pathological changes of COVID-19 associated deaths and even no consensus on the criteria for determining the cause of death. The investigation of the basic pathological changes and progression of the disease is helpful to guide the clinical treatment and the development of therapeutic drugs. This paper reviews the autopsy reports and related literature published worldwide from February 2020 to June 2023, with a clear number of autopsy cases and corresponding pathological changes of vital organs as the inclusion criteria. A total of 1 111 autopsy cases from 65 papers in 18 countries are included. Pathological manifestations and causes of death are classified and statistically analyzed, common pathological changes of COVID-19 are summarized, and analytical conclusions are drawn, suggesting that COVID-19 infection can cause life-threatening pathological changes in vital organs. On the basis of different health levels of infected groups, the direct cause of death is mainly severe lung damage and secondary systemic multiple organ failure.
Topics: Humans; SARS-CoV-2; COVID-19; Cause of Death; Lung; Autopsy
PubMed: 38228478
DOI: 10.12116/j.issn.1004-5619.2023.430703 -
Frontiers in Immunology 2023Nowadays, people have relaxed their vigilance against COVID-19 due to its declining infection numbers and attenuated virulence. However, COVID-19 still needs to be... (Review)
Review
Nowadays, people have relaxed their vigilance against COVID-19 due to its declining infection numbers and attenuated virulence. However, COVID-19 still needs to be concern due to its emerging variants, the relaxation of restrictions as well as breakthrough infections. During the period of the COVID-19 infection, the imbalanced and hyper-responsive immune system plays a critical role in its pathogenesis. Macrophage Activation Syndrome (MAS) is a fatal complication of immune system disease, which is caused by the excessive activation and proliferation of macrophages and cytotoxic T cells (CTL). COVID-19-related hyperinflammation shares common clinical features with the above MAS symptoms, such as hypercytokinemia, hyperferritinemia, and coagulopathy. In MAS, immune exhaustion or defective anti-viral responses leads to the inadequate cytolytic capacity of CTL which contributes to prolonged interaction between CTL, APCs and macrophages. It is possible that the same process also occurred in COVID-19 patients, and further led to a cytokine storm confined to the lungs. It is associated with the poor prognosis of severe patients such as multiple organ failure and even death. The main difference of cytokine storm is that in COVID-19 pneumonia is mainly the specific damage of the lung, while in MAS is easy to develop into a systemic. The attractive therapeutic approach to prevent MAS in COVID-19 mainly includes antiviral, antibiotics, convalescent plasma (CP) therapy and hemadsorption, extensive immunosuppressive agents, and cytokine-targeted therapies. Here, we discuss the role of the therapeutic approaches mentioned above in the two diseases. And we found that the treatment effect of the same therapeutic approach is different.
Topics: Humans; COVID-19; SARS-CoV-2; Macrophage Activation Syndrome; Cytokine Release Syndrome; COVID-19 Serotherapy
PubMed: 37483597
DOI: 10.3389/fimmu.2023.1200289 -
Frontiers in Medicine 2023Heatstroke can cause multiple organ failure and systemic inflammatory response syndrome as the body temperature rises beyond the body's ability to regulate temperature... (Review)
Review
Heatstroke can cause multiple organ failure and systemic inflammatory response syndrome as the body temperature rises beyond the body's ability to regulate temperature in a hot environment. Previous studies have indicated that heatstroke-induced acute kidney injury (AKI) can lead to chronic kidney disease. Therefore, there is an urgent need to elucidate the mechanism of heatstroke-induced AKI and to establish methods for its prevention and treatment. Recent reports have revealed that innate immunity, including neutrophils, macrophages, lymphocytes, and mast cells, is deeply involved in heat-induced AKI. In this review, we will discuss the roles of each immune cell in heat-induced renal injury and their potential therapeutic use.
PubMed: 37614951
DOI: 10.3389/fmed.2023.1250457 -
Acute and Critical Care Nov 2023Intra-abdominal hypertension can have severe consequences, including abdominal compartment syndrome, which can contribute to multi-organ failure. An increase in...
Intra-abdominal hypertension can have severe consequences, including abdominal compartment syndrome, which can contribute to multi-organ failure. An increase in intra-abdominal hypertension is influenced by factors such as diminished abdominal wall compliance, increased intraluminal content, and certain systemic conditions. Regular measurement of intra-abdominal pressure is essential, and particular attention must be paid to patient positioning. Nonsurgical treatments, such as decompression of intraluminal content using a nasogastric tube, percutaneous drainage, and fluid balance optimization, play crucial roles. Additionally, point-of-care ultrasonography aids in the diagnosis and treatment of intra-abdominal hypertension. Emphasizing the importance of regular measurements, timely decompressive laparotomy is a definitive, but complex, treatment option. Balancing the urgency of surgical intervention against potential postoperative complications is challenging.
PubMed: 38052507
DOI: 10.4266/acc.2023.01263 -
International Journal of Molecular... Dec 2023Sepsis is a systemic inflammatory syndrome that results in multiple-organ failure caused by a dysregulated host immune response to microbial infection. Astragali...
Sepsis is a systemic inflammatory syndrome that results in multiple-organ failure caused by a dysregulated host immune response to microbial infection. Astragali complanati semen extract (ACSE) exhibits pharmacological activities, including antioxidant, anticancer, antiaging, and anti-diabetes effects. It is widely used in traditional medicine to treat liver and kidney diseases; however, the protective effect of ACSE on sepsis and its mechanisms are unknown. In the present study, we investigated the anti-inflammatory effects and potential mechanisms of the action of ACSE on sepsis. We show that ACSE improved survival rates in mouse models of acute sepsis induced by CLP (cecal ligation and puncture) and LPS stimulation. ACSE administration decreased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in sepsis-induced mice. Furthermore, ACSE reduced the levels of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the serum of septic mice. ACSE treatment inhibited the expression of these proinflammatory genes in LPS-stimulated J774 macrophages. Moreover, ACSE inhibited the phosphorylation of the IκB kinase (IKK) and the nuclear translocation of p65 NF-κB by LPS stimulation in macrophages. These results reveal the mechanism underlying the protective effect of ACSE against sepsis by inhibiting NF-κB activation and suggest that ACSE could be a potential therapeutic candidate to treat acute inflammatory diseases.
Topics: Animals; Mice; Shock, Septic; Lipopolysaccharides; NF-kappa B; Sepsis; Astragalus Plant; Ethanol; Anti-Inflammatory Agents
PubMed: 38203555
DOI: 10.3390/ijms25010384 -
Aging Aug 2023The respiratory and cardiovascular systems are often the most severely impacted by the rapid onset of sepsis, which can lead to multiple organ failure. The mortality has...
The respiratory and cardiovascular systems are often the most severely impacted by the rapid onset of sepsis, which can lead to multiple organ failure. The mortality has ranged from 10 to 40% when it has evolved into septic shock. This study sought to demonstrate the potential and role of Hmgcs2 in safeguarding against cardiovascular harm in septic mouse models. The cecal ligament and puncture (CLP) model was used to induce sepsis in C57BL/6 mice, with Hmgcs2 expression in the myocardium of the mice being heightened and inflammatory factors being augmented. Subsequently, we utilized ASOs to silence the hmgcs2 gene, and found that silencing accelerated septic myocardial injury and cardiac dysfunction in CLP mice models. In contrast, hmgcs2 attenuated inflammation and apoptosis and protected against septic cardiomyopathy in murine septicemia models. Src production, spurred on by Hmgcs2, triggered the PI3K/Akt pathway and augmented M2 macrophage polarization. Moreover, the inhibition of M2 polarization by an Src antagonist significantly contributed to apoptosis of cardiomyocytes. Our research revealed that Hmgcs2 inhibited the activation of pro-inflammatory macrophages and, through Src-dependent activation of PI3K/Akt pathway, promoted the anti-inflammatory phenotype, thus safeguarding myocardial damage from sepsis. This offers a novel theoretical basis for prevention and treatment of infectious complications.
Topics: Mice; Animals; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Mice, Inbred C57BL; Macrophages; Myocytes, Cardiac; Heart Injuries; Sepsis
PubMed: 37561521
DOI: 10.18632/aging.204944