RESUMEN
In acute lung injury (ALI), a severe insult induces a hyperinflammatory state in the lungs. The mortality rate of severe ALI remains high, and novel mechanistic insights are required to improve therapeutic strategies. Endothelin-2 (Edn2), the least studied isoform of endothelin, is involved in lung physiology and development and can be affected by various factors. One of them is inflammation, and another isoform of endothelin, endothelin-1 (Edn1), affects lung inflammatory responses. Considering the importance of Edn2 in the lungs and how Edn2 works through the same receptors as Edn1, we postulated that Edn2 may affect inflammatory responses that are central to ALI pathophysiology. In this study, we performed 24 hours intratracheal lipopolysaccharide (LPS) instillation or PBS control as an in vivo ALI model in eight-week-old conditional Edn2 knockout mice (Edn2-iKO), with Edn2-floxed mice as controls. Bronchoalveolar lavage (BAL) fluid and tissue were collected after exsanguination and analyzed for its cellular, molecular, functional, and histological inflammatory phenotypes. We found that Edn2-iKO mice displayed a reduced pro-neutrophilic inflammatory phenotype even after acute LPS treatment, shown by the reduction in the overall protein concentration and neutrophil count in bronchoalveolar lavage fluids. Further investigation revealed a reduction in mRNA interferon gamma (IFNγ) level of Edn2-iKO lungs and suppression of its downstream signaling, including phosphorylated level of STAT1 and IL-1ß secretion, leading to reduced NFĸB activation. To conclude, Edn2 deletion suppressed acute lung inflammation by reducing neutrophil-mediated IFNγ/STAT1/IL-1ß/NFĸB signaling cascade. Targeting Edn2 signaling may be beneficial for the development of novel treatment options for ALI.
Asunto(s)
Lesión Pulmonar Aguda , Endotelina-2 , Animales , Ratones , Endotelina-2/metabolismo , Lipopolisacáridos , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Pulmón/patología , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/uso terapéuticoRESUMEN
Advances in technology and biomedical knowledge have led to the effective diagnosis and treatment of an increasing number of rare diseases. Pulmonary arterial hypertension (PAH) is a rare disorder of the pulmonary vasculature that is associated with high mortality and morbidity rates. Although significant progress has been made in understanding PAH and its diagnosis and treatment, numerous unanswered questions remain regarding pulmonary vascular remodeling, a major factor contributing to the increase in pulmonary arterial pressure. Here, we discuss the role of activins and inhibins, both of which belong to the TGF-ß superfamily, in PAH development. We examine how these relate to signaling pathways implicated in PAH pathogenesis. Furthermore, we discuss how activin/inhibin-targeting drugs, particularly sotatercep, affect pathophysiology, as these target the afore-mentioned specific pathway. We highlight activin/inhibin signaling as a critical mediator of PAH development that is to be targeted for therapeutic gain, potentially improving patient outcomes in the future.
Asunto(s)
Inhibinas , Hipertensión Arterial Pulmonar , Humanos , Inhibinas/metabolismo , Activinas/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Diabetes mellitus (DM) increases risk of coronary artery disease (CAD). Endothelin-1 (ET-1) is a potential biomarker of endothelial dysfunction. This study aimed to evaluate ET-1 level in CAD patients and its relationship with DM. The cross-sectional design included subjects with angiographically proven CAD and controls among Indonesian. DM was defined by medical history and anti-diabetics use. Serum ET-1 level was measured in both subject groups. We recruited 305 subjects, 183 CAD patients and 122 controls. CAD subjects had higher percentage of males, DM, hypertension, dyslipidemia, smoking, family history of cardiovascular disease, and obesity. ET-1 level was significantly higher in CAD than in controls (2.44 ± 1.49 pg/mL vs. 1.76 ± 0.83 pg/mL; p < 0.001). Increased ET-1 level was significantly associated with DM and dyslipidemia. The highest ET-1 level was observed in CAD with DM, followed by CAD non-DM (2.79 ± 1.63 pg/mL vs. 2.29 ± 1.40 pg/mL; p = 0.023). Among controls, ET-1 level was the lowest in non-DM subjects. Female CAD had higher proportion of DM; however, ET-1 level was similar to male CAD with DM. In conclusion, an increased ET-1 level was significantly associated with DM in patients with CAD. Further research should investigate the potential role of ET-1 receptor antagonists in the secondary prevention of CAD with DM.
Asunto(s)
Enfermedad de la Arteria Coronaria , Diabetes Mellitus , Dislipidemias , Humanos , Masculino , Femenino , Enfermedad de la Arteria Coronaria/epidemiología , Endotelina-1 , Estudios Transversales , Indonesia/epidemiología , Diabetes Mellitus/epidemiología , Dislipidemias/complicaciones , Dislipidemias/epidemiología , Factores de RiesgoRESUMEN
Melioidosis, an infectious disease caused by Burkholderia pseudomallei, has recently gained importance as an emerging infectious disease in Indonesia. Reports of this infection in Indonesia are limited, although cases have been reported in Makassar, South Sulawesi. We report a case of cutaneous melioidosis caused by pan-drug-resistant, moderate biofilm-producer strain of B. pseudomallei in a diabetic patient. To the best of our knowledge, this is the first case of melioidosis caused by multidrug resistant and biofilm-former strain of B. pseudomallei being reported from Yogyakarta Province, Indonesia. The patient was successfully treated with abscess drainage and debridement, including total contact casting and no antibiotic treatment.