Irma Mahmutovic Persson

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Biological- and imaging biomarkers of edema and fibrosis in a rat model of drug-induced interstitial lung disease (DIILD)

Irma Mahmutovic Persson Hanna Falk Håkansson Anders Örbom Per‐Ola Önnervik Janne Persson

A large number of systemically administered drugs have the potential to cause DIILD. We aim to characterize a model of DIILD in the rat and develop imaging biomarkers for detection and quantification of DIILD. Methods: Sprague-Dawley rats received one single dose of intratracheal bleomycin and were longitudinally imaged at day 0, 3, 7, 14, 21 and 28 post dosing, applying imaging techniques MRI and PET/CT. Bronchoalveolar lavage fluid (BALF) was analyzed for total protein and inflammatory cells. Lungs were taken for further analyses by histology, and stained for inflammation and collagen deposition. Results: Bleomycin induced significant increase in total protein concentration and total cell count in BALF, peaking at day3 (p>0.001) and day7 (p>0.001) compared to control, respectively. The lesion measured by MRI and the FDG-PET signal in the lungs of bleomycin challenged rats was significantly increased during day3-14, peaking at day7. Two subgroups of animals were identified as low- and high responders to bleomycin challenge, by their different change in total lung volume. Both groups showed signs of inflammation initially, while at later time points the low-responder group recovered towards control, and the high-responder group showed progressive fibrosis with significant increase of lesion volume (p<0.001), compared to control. Conclusion: Bleomycin-induced lung injury with MRI and PET readout in rats, is an adequate and translational animal model for DIILD studies. The scenario comprised different disease responses, with different fractions of inflammation and fibrosis. Thereby, this study improved the understanding biological- and imaging biomarkers in DIILD.

Histology

10.1183/13993003.congress-2019.pa2417

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House dust mite impairs antiviral response in asthma exacerbation models through its effects on TLR3

Allergy (2018)

Hamid Akbarshahi Mandy Menzel Sangeetha Ramu Irma Mahmutovic Persson Leif Bjermer

Impaired antiviral interferon expression may be involved in asthma exacerbations commonly caused by rhinovirus infections. Allergy is a known risk factor for viral-induced asthma exacerbation, but little is known whether allergens may affect interferon responses.Our hypothesis is that house dust mite (HDM) impairs viral stimulus-induced antiviral signalling.Experimental asthma exacerbations were produced in vitro in human bronchial epithelial cells (HBECs) and in mice using sequential challenges with HDM and a viral infection mimic, Poly(I:C). We examined rhinovirus pattern recognition receptors (PRRs) signalling pathways and potential mechanisms of impaired interferon response.HBECs and mice exposed to HDM prior to Poly(I:C) exhibited a reduced antiviral response compared to Poly(I:C) alone, including reduced IFN-β, IFN-λ, TLR3, RIG-I, MDA5, IRF-3 and IRF-7. Heat inactivation of HDM partially restored the TLR3-induced interferon response in vitro and in vivo. Our HBEC-data further showed that HDM directly affects TLR3 signalling by targeting the receptor glycosylation level.Direct effects of allergens such as HDM on PRRs can present as potential mechanism for defective antiviral airway responses. Accordingly, therapeutic measures targeting inhibitory effects of allergens on antiviral PRRs may find use as a strategy to boost antiviral response and ameliorate exacerbations in asthmatic patients.

Rhinovirus

TLR3

TLR7

10.1111/all.13378

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Citations (43)

Spatial lung imaging in clinical and translational settings

Breathe (2024)

Irma Mahmutovic Persson Gracijela Božović Gunilla Westergren‐Thorsson Sara Rolandsson Enes

For many severe lung diseases, non-invasive biomarkers from imaging could improve early detection of lung injury or disease onset, establish a diagnosis, or help follow-up disease progression and treatment strategies. Imaging of the thorax and lung is challenging due to its size, respiration movement, transferred cardiac pulsation, vast density range and gravitation sensitivity. However, there is extensive ongoing research in this fast-evolving field. Recent improvements in spatial imaging have allowed us to study the three-dimensional structure of the lung, providing both spatial architecture and transcriptomic information at single-cell resolution. This fast progression, however, comes with several challenges, including significant image file storage and network capacity issues, increased costs, data processing and analysis, the role of artificial intelligence and machine learning, and mechanisms to combine several modalities. In this review, we provide an overview of advances and current issues in the field of spatial lung imaging.

Modalities

10.1183/20734735.0224-2023

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DsRNA-Induced TSLP Expression And Neutrophilia In Mouse Asthma Exacerbation Model

Irma Mahmutovic Persson Angelica Brandelius Lena Uller

Neutrophilia

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a5385

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Supplementary Material for: NFκB1 Dichotomously Regulates Pro-Inflammatory and Antiviral Responses in Asthma

Figshare (2021)

Mandy Menzel Hamid Akbarshahi Irma Mahmutovic Persson Cecilia Andersson Manoj Puthia

Asthma exacerbations are commonly triggered by rhinovirus infections. Viruses can activate the NFκB pathway resulting in airway inflammation and increased Th2 cytokine expression. NFκB signaling is also involved in early activation of IFNβ, which is a central mediator of antiviral responses to rhinovirus infection. Using a mouse model, this study tests our hypothesis that NFκB signaling is involved in impaired IFNβ production at viral-induced asthma exacerbations. C57BL/6 wild-type and NFκB1^−/− mice were challenged with house dust mite for 3 weeks and were subsequently stimulated with the rhinoviral mimic poly(I:C). General lung inflammatory parameters and levels of the Th2 upstream cytokine IL-33 were measured after allergen challenge. At exacerbation, production of IFNβ and antiviral proteins as well as gene expression of pattern recognition receptors and IRF3/IRF7 was assessed. In the asthma exacerbation mouse model, lack of NFκB1 resulted in lower levels of IL-33 after allergen challenge alone and was associated with reduced eosinophilia. At exacerbation, mice deficient in NFκB1 exhibited enhanced expression of IFNβ and antiviral proteins. This was accompanied by increased IRF3/IRF7 expression and induction of pattern recognition receptor expression. In a human asthma dataset, a negative correlation between IRF3 and NFκB1 expression was observed. NFκB may impair antiviral responses at exacerbation, possibly by reducing expression of the transcription factors IRF3/IRF7. These findings suggest a therapeutic potential for targeting NFκB pathways at viral infection-induced exacerbations.

Inflammatory response

10.6084/m9.figshare.15065697

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IL-1β mediates lung neutrophilia and IL-33 expression in a mouse model of viral-induced asthma exacerbation

Respiratory Research (2018)

Irma Mahmutovic Persson Mandy Menzel Sangeetha Ramu Samuel Cerps Hamid Akbarshahi

Viral-induced asthma exacerbations, which exhibit both Th1-type neutrophilia and Th2-type inflammation, associate with secretion of Interleukin (IL)-1β. IL-1β induces neutrophilic inflammation. It may also increase Th2-type cytokine expression. We hypothesised that IL-1β is causally involved in both Th1 and Th2 features of asthma exacerbations. This hypothesis is tested in our mouse model of viral stimulus-induced asthma exacerbation. Wild-type (WT) and IL-1β deficient (IL-1β−/−) mice received house dust mite (HDM) or saline intranasally during three weeks followed by intranasal dsRNA (PolyI:C molecule known for its rhinovirus infection mimic) for three consecutive days to provoke exacerbation. Bronchoalveolar lavage fluid was analysed for inflammatory cells and total protein. Lung tissues were stained for neutrophilic inflammation and IL-33. Tissue homogenates were analysed for mRNA expression of Muc5ac, CXCL1/KC, TNF-α, CCL5, IL-25, TSLP, IL-33, IL-1β, CCL11 and CCL2 using RT-qPCR. Expression of IL-1β, neutrophil chemoattractants, CXCL1 and CCL5, the Th2-upstream cytokine IL-33, and Muc5ac were induced at exacerbation in WT mice and were significantly inhibited in IL-1β−/− mice at exacerbation. Effects of HDM alone were not reduced in IL-1β-deficient mice. Without being involved in the baseline HDM-induced allergic asthma, IL-1β signalling was required to induce neutrophil chemotactic factors, IL-33, and Muc5ac expression at viral stimulus-induced exacerbation. We suggest that IL-1β has a role both in neutrophilic and Th2 inflammation at viral-induced asthma exacerbations.

CXCL1

Neutrophilia

CCL5

Thymic stromal lymphopoietin

Rhinovirus

CCL11

10.1186/s12931-018-0725-z

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Citations (97)

NFκB1 Dichotomously Regulates Pro-Inflammatory and Antiviral Responses in Asthma

Journal of Innate Immunity (2021)

Mandy Menzel Hamid Akbarshahi Irma Mahmutovic Persson Cecilia Andersson Manoj Puthia

Asthma exacerbations are commonly triggered by rhinovirus infections. Viruses can activate the NFκB pathway resulting in airway inflammation and increased Th2 cytokine expression. NFκB signaling is also involved in early activation of IFNβ, which is a central mediator of antiviral responses to rhinovirus infection. Using a mouse model, this study tests our hypothesis that NFκB signaling is involved in impaired IFNβ production at viral-induced asthma exacerbations. C57BL/6 wild-type and NFκB1<sup>−/−</sup> mice were challenged with house dust mite for 3 weeks and were subsequently stimulated with the rhinoviral mimic poly(I:C). General lung inflammatory parameters and levels of the Th2 upstream cytokine IL-33 were measured after allergen challenge. At exacerbation, production of IFNβ and antiviral proteins as well as gene expression of pattern recognition receptors and IRF3/IRF7 was assessed. In the asthma exacerbation mouse model, lack of NFκB1 resulted in lower levels of IL-33 after allergen challenge alone and was associated with reduced eosinophilia. At exacerbation, mice deficient in NFκB1 exhibited enhanced expression of IFNβ and antiviral proteins. This was accompanied by increased IRF3/IRF7 expression and induction of pattern recognition receptor expression. In a human asthma dataset, a negative correlation between IRF3 and NFκB1 expression was observed. NFκB may impair antiviral responses at exacerbation, possibly by reducing expression of the transcription factors IRF3/IRF7. These findings suggest a therapeutic potential for targeting NFκB pathways at viral infection-induced exacerbations.

IRF3

Rhinovirus

IRF7

10.1159/000517847

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Citations (6)

Nanoscale structural alteration of collagen fibril in response to strain and bleomycin injury

Research Square (Research Square) (2024)

Richard T. Deyhle Robin Krüger Luca Fardin Irma Mahmutovic Persson J. L. Cercos-Pita

Abstract The link between the structural organization of the fibrillar components of lung extracellular matrix (ECM), local tissue stiffness and global viscoelastic behavior is not known. Here we investigated the effect of injurious mechanical ventilation on the local lung tissue stiffness using 4D synchrotron phase-contrast micro-CT, in normal lung and 7 days after intratracheal bleomycin induced lung injury in anesthetized rats. Quantitative maps of local lung strain (e) were computed within aerated lung acini, using a stepwise image registration method. Fibrillar organization of collagen and elastin at the nanoscale was measured using synchrotron small-angle x-ray scattering (SAXS). Local microscopic tissue e was reduced in the aerated acini of normal lungs post injurious ventilation and in bleomycin-injured lungs and was associated with an increase in dynamic elastance (H). The scattering peak angle (q) which is inversely related to fibril d-spacing, was decreased by injurious ventilation indicating an elongation of the collagen fibrils in both normal and bleomycin-injured lung. There was a positive relationship between collagen periodicity and global tissue elastance, while an inverse relation was observed with tissue hysteresis. Our data demonstrate the effect of both bleomycin-induced lung injury and high-strain mechanical ventilation on the nanoscale fibrillar organization of collagen and for the first time, a link between collagen d-spacing and global lung tissue stiffening and viscoelastic behavior.

Collagen fibril

Strain (injury)

10.21203/rs.3.rs-5683359/v1

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Interferon-β deficiency at asthma exacerbation promotes MLKL mediated necroptosis

Scientific Reports (2018)

Samuel Cerps Mandy Menzel Irma Mahmutovic Persson Leif Bjermer Hamid Akbarshahi

Defective production of antiviral interferon (IFN)-β is thought to contribute to rhinovirus-induced asthma exacerbations. These exacerbations are associated with elevated lung levels of lactate dehydrogenase (LDH), indicating occurrence of cell necrosis. We thus hypothesized that reduced lung IFN-β could contribute to necrotic cell death in a model of asthma exacerbations. Wild-type and IFN-β-/- mice were given saline or house dust mite (HDM) intranasally for 3 weeks to induce inflammation. Double-stranded RNA (dsRNA) was then given for additional 3 days to induce exacerbation. HDM induced an eosinophilic inflammation, which was not associated with increased expression of cleaved caspase-3, cleaved PARP or elevated bronchoalveolar lavage fluid (BALF) LDH levels in wild-type. However, exacerbation evoked by HDM + dsRNA challenges increased BALF levels of LDH, apoptotic markers and the necroptotic markers receptor-interacting protein (RIP)-3 and phosphorylation of mixed linage kinase domain-like protein (pMLKL), compared to HDM + saline. Absence of IFN-β at exacerbation further increased BALF LDH and protein expression of pMLKL compared to wild-type. We demonstrate that cell death markers are increased at viral stimulus-induced exacerbation in mouse lungs, and that absence of IFN-β augments markers of necroptotic cell death at exacerbation. Our data thus suggest a novel role of deficient IFN-β production at viral-induced exacerbation.

10.1038/s41598-018-22557-6

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Citations (15)

Acute renal failure - basic research

NDT Plus (2009)

Stefania Bruno Cristina Grange Maria Chiara Deregibus Raffaele Calogero Silvia Saviozzi

10.1093/ndtplus/2.s2.41

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