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- Polinati, P. P., et al.
(författare)
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Patient-specific induced pluripotent stem cell-derived RPE cells : Understanding the pathogenesis of retinopathy in long-chain 3-hydroxyacyl-CoA dehydrogenase deiciency
- 2015
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Ingår i: Investigative Ophthalmology and Visual Science. - : Lippincott-Raven Publishers. - 0146-0404 .- 1552-5783. ; 56:5, s. 3371-3382
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Retinopathy is an important manifestation of trifunctional protein (TFP) deficiencies but not of other defects of fatty acid oxidation. The common homozygous mutation in the TFP α-subunit gene HADHA (hydroxyacyl-CoA dehydrogenase), c.1528G>C, affects the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity of TFP and blindness in infancy. The pathogenesis of the retinopathy is unknown. This study aimed to utilize human induced pluripotent stem cell (hiPSC) technology to create a disease model for the disorder, and to derive clues for retinopathy pathogenesis.Methods: We implemented hiPSC technology to generate LCHAD deficiency (LCHADD) patient-specific retinal pigment epithelial (RPE) monolayers. These patient and control RPEs were extensively characterized for function and structure, as well as for lipid composition by mass spectrometry.Results: The hiPSC-derived RPE monolayers of patients and controls were functional, as they both were able to phagocytose the photoreceptor outer segments in vitro. Interestingly, the patient RPEs had intense cytoplasmic neutral lipid accumulation, and lipidomic analysis revealed an increased triglyceride accumulation. Further, patient RPEs were small and irregular in shape, and their tight junctions were disorganized. Their ultrastructure showed decreased pigmentation, few melanosomes, and more melanolysosomes.Conclusions: We demonstrate that the RPE cell model reveals novel early pathogenic changes in LCHADD retinopathy, with robust lipid accumulation, inefficient pigmentation that is evident soon after differentiation, and a defect in forming tight junctions inducing apoptosis. We propose that LCHADD-RPEs are an important model for mitochondrial TFP retinopathy, and that their early pathogenic changes contribute to infantile blindness of LCHADD.
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- Hisinger-Molkanen, H., et al.
(författare)
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The combined effect of exposures to vapours, gases, dusts, fumes and tobacco smoke on current asthma
- 2022
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Ingår i: Clinical Respiratory Journal. - : Wiley. - 1752-6981 .- 1752-699X. ; 16:6, s. 467-474
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Tidskriftsartikel (refereegranskat)abstract
- Smoking, exposure to environmental tobacco smoke (ETS) and occupational exposure to vapours, gases, dusts or fumes (VGDF) increase asthma symptoms. The impact of combined exposure is less well established. We aimed to evaluate the risk of combined exposure to smoking, ETS and VGDF on the prevalence of current asthma and asthma-related symptoms with a postal survey among a random population of 16,000 adults, aged 20-69 years (response rate 51.5%). The 836 responders with physician-diagnosed asthma were included in the analysis. Of them, 81.9% had current asthma defined as physician-diagnosed asthma with current asthma medication use or reported symptoms. There was a consistently increasing trend in the prevalence of current asthma by increased exposure. The highest prevalence of multiple symptoms was in smokers with VGDF exposure (92.1%) compared to the unexposed (73.9%, p = 0.001). In logistic regression analysis, combined exposure to several exposures increased the risk in all analysed symptoms (p = 0.002-0.007). In conclusion, smoking and exposure to ETS or VGDF increased the prevalence of current asthma and multiple symptoms. The combined exposure carried the highest risk. Preventive strategies are called for to mitigate exposure to tobacco smoke and VGDF.
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- Niemela, T., et al.
(författare)
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Relationship Between Soluble Urokinase Plasminogen Activator Receptor (suPAR) and Disease Outcome in Adult-Onset Asthma
- 2022
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Ingår i: Journal of Asthma and Allergy. - 1178-6965. ; 15, s. 579-593
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Tidskriftsartikel (refereegranskat)abstract
- Background: Soluble urokinase plasminogen activator receptor (suPAR) has emerged as a novel biomarker for various inflammatory conditions and has been proposed to associate with the severity of asthma. However, the relationship between suPAR and clinical asthma features is poorly understood. Objective: To examine associations of serum suPAR levels with clinical characteristics of asthma and to define the phenotype with high suPAR levels in patients with adult-onset asthma. Methods: Serum suPAR levels were measured with ELISA from patients with adult-onset asthma participating in the 12-year followup visit in the Seinajoki Adult Asthma Study. Results: In total, 201 patients were divided into quartiles according to suPAR values. High suPAR patients had more severe asthma symptoms and poorer asthma control. They also had higher levels of interleukin 8 (IL-8), interleukin 6 (IL-6), matrix metalloproteinase 9 (MMP-9), and blood neutrophil counts than those with low suPAR levels. The use of high-dose inhaled and oral corticosteroids was more common in patients with elevated suPAR. Such patients also had visited healthcare more frequently during the follow-up period, had more comorbidities, and were physically less active than those with low suPAR levels. The above-mentioned results remained similar after excluding the patients with co-existing COPD; only association to hospitalizations was lost. In multivariable binary regression analyses, the highest suPAR quartile was associated with higher cumulative dispensed oral corticosteroid use, more severe symptoms, and uncontrolled asthma. Conclusion: High suPAR levels occur in uncontrolled adult-onset asthma patients characterized by neutrophilic inflammation, high corticosteroid use, frequent healthcare visits, and multimorbidity with unhealthy lifestyle. This biomarker could be useful in determining asthma phenotypes and target new asthma treatments.
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