1,721,037 research outputs found
Pirfenidone treatment in a patient with IPF and possible initial hypersensitivity pulmonitis
No full textThe diagnosis of idiopathic pulmonary fibrosis (IPF) requires exclusion of other known causes of interstitial lung disease (ILD) (e.g., domestic and occupational environmental exposures, systemic connective tissue disease, and drug toxicity), the presence of a ‘usual interstitial pneumonia’ (UIP) pattern on high resolu- tion computed tomography (HRCT), and specific combinations of HRCT and histopathologic patterns in pa- tients subjected to surgical lung biopsy (SLB). A clear diagnosis and early treatment with currently the only ap- proved anti-fibrotic drug, pirfenidone, represents the standard of care for the treatment of mild-to-moderate IPF. This case report describes a patient with possible initial hypersensitivity pneumonitis and subsequent di- agnosis of IPF with late development of pulmonary hypertension, and who was a candidate for lung transplan- tation. The patient showed slow progression of IPF during pirfenidone treatment in the CAPACITY and RE-CAP studies
Glycogen synthase kinase-3 (GSK-3) in the pathogenesis of pulmonary fibrosis: what we know from the mouse model
Full text linkIntroduction: Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by an aberrant interstitial deposition of collagen in the lung parenchyma, leading to progressive lung function impairment. Repeated injuries to the alveolar epithelium are believed to lead to an imbalance of the extracellular matrix (ECM) turnover supported by metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). The kinase GSK-3 is a mediator of the cytokine homeostasis and favors the production of pro-inflammatory mediators. Its specific inhibitor, SB216763, displayed anti-inflammatory and anti-fibrotic properties of in a mouse model of Bleomycine (BLM)-induced pulmonary fibrosis. Furthermore, GSK-3 seems to be involved in the epithelial to mesenchimal transition (EMT). The purpose of this study was to assess the expression of MMP9, TIMP1, MMP2 and and TIMP2 in the early inflammatory response and in the late fibrosis induced by BLM in a mouse model of pulmonary fibrosis. Next goal was to elucidate whether the in vivo treatment with SB216763 could modulate MMPs activity and their balance with TIMPs. Moreover, in vitro experiments were aimed to identify the signal pathways through which GSK-3 can modulate MMPs and TIMPs.
Methods: Cohorts of C57BL6 mice (12 weeks old) were randomized to receive intratracheal instillation of either saline (PBS), or BLM alone, or BLM in association with SB216763. The inhibitor was administered intraperitoneally the day after BLM and every 48 hours up to the sacrifice on day 7 (inflammatory phase) or 28 (fibrotic phase), when bronchoalveolar lavage (BAL) was performed and lungs harvested. MMP9 and MMP2 activity was measured by gel zymography in BAL fluid (BALF). MMPs and TIMPs expression levels were evaluated by Real Time-PCR and Western Blotting. Their tissue localization was evaluated by IHC analysis. In vitro experiments were performed using A549 cells as epithelial model, assessing expression and activity of MMPs downstream of TNFα, with and without GSK-3 silencing by siRNA.
Results: MMP9 and MMP2 levels were elevated in BALF from BLM-treated mice at day 7. At this time point, the inflammatory cells recruited in the intra-alveolar spaces were alveolar macrophages (AMs), lymphocytes and neutrophils. Furthermore, the lung IHC staining indicated a strong positivity for MMP9, MMP2, TIMP1 and TIMP2 in interstitial AM (iAM) and, specifically, in injured and cuboidalized epithelium. BLM-treated mice sacrificed at day 28 presented high levels of MMP2 and TIMP1 and low levels of MMP9 in the BALF. Interestingly, in vivo GSK-3 inhibition reduced MMP9, MMP2 and TIMP1 levels in the BALF and their positivity in iAMs and in epithelium. Moreover, in vitro experiments performed with A549 cells, as epithelial model, demonstrated that GSK-3α and GSK-3β silencing increased MMP9 expression after stimulation with the pro-inflammatory cytokine TNFα. This effect was achieved by the interaction of GSK-3 with NF-kB and ERK signalling transduction pathway.
Conclusions: Our mouse model of BLM-induced pulmonary fibrosis clearly showed an imbalance between MMPs and TIMPs during inflammation and fibrosis. Importantly, we proposed GSK-3 as a crucial mediator of their expression in AMs and in damaged epithelium. Next, in vitro results with A549 cells suggested that GSK-3 silencing induce MMP-9 secretion, downstream of TNFα, in a p65-mediated and ERK1,2 dependent manner
Advances in understanding the immunopathology of sarcoidosis and implications on therapy
No full textSarcoidosis is a multi-systemic granulomatous disease of unknown aetiology. Ethnicity and environmental factors may influence disease incidence, phenotype and severity. Areas covered: Predisposing genes are mainly involved in T cell and macrophage function, antigen presentation and recognition, and extra-cellular matrix turnover. No definitive relationship has been established with any proposed external trigger. A Th1/Th17-driven inflammatory process, involving macrophages both as antigen-presenting cells and key effectors, represent the main feature of the acute disease. Less is known about the determinants of clinical remission versus chronic disease and fibrosis. Treatment strategies mainly rely on immunosuppression with steroids and/or steroid-sparing drugs, in order to switch off acute inflammation and prevent disease evolution. Anti-TNF drugs represent a valuable option for chronic refractory diseases; no specific anti-fibrotic treatment is currently available. Expert commentary: Future therapeutic strategies will have to specifically target mediators and pathways involved in the chronic and fibrotic phase of sarcoidosis, focusing on genetic/genomic biomarkers and predictors of disease phenotype
Immunology of sarcoidosis: old companions, new relationships
No full textPurpose of review: The immune determinants of granuloma formation and disease progression in sarcoidosis have not been completely disclosed, and the role of both innate and the adaptive immunity is still under investigation.Recent findings: M2 macrophage polarization, previously thought to be a specific feature of a progressing and fibrosing disease, has been related to the initial steps of granuloma formation both in animal and in-vitro models. The dysregulation of specific metabolic pathways and autophagy has been associated with disease activity and progression. T cells have been reported to be strongly influenced by a macrophage-driven microenvironment and more dangerous when acquiring hybrid phenotypes (e.g. Th17.1) or even becoming anergic, leading to disease chronicization. Locally released serum amyloid A was suggested to induce a more pro-inflammatory Th17 transcription program. The possible role of in-situ humoral immunity and bone marrow-derived mesenchymal stromal cells has also been highlighted.Summary: Evidence points at microenvironment and cell functional features rather than cell polarization or differentiation as determinants of pathogenesis. In terms of therapeutic implications, future advances will rely on molecular disease profiling, aiming at personalized and combined therapeutic approaches
Editorial comment on “Expected impact of immunomodulatory agents during pregnancy: A newborn's perspective”
No full textThe broad spectrum of lung diseases in primary antibody deficiencies
Full text linkHuman primary immunodeficiency diseases (PIDs) represent a heterogeneous group of more than 350 disorders. They are rare diseases, but their global incidence is more relevant than generally thought. The underlying defect may involve different branches of the innate and/or adaptive immune response. Thus, the clinical picture may range from severe phenotypes characterised by a broad spectrum of infections to milder infectious phenotypes due to more selective (and frequent) immune defects. Moreover, infections may not be the main clinical features in some PIDs that might present with autoimmunity, auto-inflammation and/or cancer. Primary antibody deficiencies (PADs) represent a small percentage of the known PIDs but they are the most frequently diagnosed, particularly in adulthood. Common variable immunodeficiency (CVID) is the most prevalent symptomatic PAD.PAD patients share a significant susceptibility to respiratory diseases that represent a relevant cause of morbidity and mortality. Pulmonary complications include acute and chronic infection-related diseases, such as pneumonia and bronchiectasis. They also include immune-mediated interstitial lung diseases, such as granulomatous-lymphocytic interstitial lung disease (GLILD) and cancer. Herein we will discuss the main pulmonary manifestations of PADs, the associated functional and imaging findings, and the relevant role of pulmonologists and chest radiologists in diagnosis and surveillance
The immunopathogenesis of sarcoidosis
Full text link: Sarcoidosis is a granulomatous multiorgan disease, thought to result from exposure to yet unidentified antigens in genetically susceptible individuals. The exaggerated inflammatory response that leads to granuloma formation is highly complex and involves the innate and adaptive immune system. Consecutive immunological studies using advanced technology have increased our understanding of aberrantly activated immune cells, mediators and pathways that influence the formation, maintenance and resolution of granulomas. Over the years, it has become increasingly clear that disease immunopathogenesis can only be understood if the clinical heterogeneity of sarcoidosis is taken into consideration, along with the distribution of immune cells in peripheral blood and involved organs. Most studies offer an immunological snapshot during disease course, while the cellular composition of both the circulation and tissue microenvironment may change over time. Despite these challenges, novel insights on the role of the immune system are continuously published, thus bringing the field forward. This review highlights current knowledge on the innate and adaptive immune responses involved in sarcoidosis pathogenesis, as well as the pathways involved in non-resolving disease and fibrosis development. Additionally, we describe proposed immunological mechanisms responsible for drug-induced sarcoid like reactions. Although many aspects of disease immunopathogenesis remain to be unraveled, the identification of crucial immune reactions in sarcoidosis may help identify new treatment targets. We therefore also discuss potential therapies and future strategies based on the latest immunological findings
Usefulness of methotrexate in relapsing idiopathic retroperitoneal fibrosis
No full textObjectives: Glucocorticoids are the mainstay for treatment of retroperitoneal fibrosis (RPF), a disease characterised by a periaortic proliferation of fibroinflammatory tissue frequently causing urinary obstruction. The therapeutic approach to patients unsuitable for steroid therapy and to relapsing cases is still undefined. Methods: In this retrospective single-centre study we evaluated 15 patients with RPF who received second-line therapy with methotrexate (MTX) between January 2011 to December 2019. Results: Fourteen out of 15 patients (93%) showed response to MTX. Two patients experienced relapse: one patient when on MTX therapy (28 months), the other, 58 months after MTX was interrupted. Liver toxicity grade 2 was documented in 2 patients and resolved with temporary dosage reduction. One patient stopped MTX autonomously because of nausea. No severe infections were recorded. Conclusions: In selected patients with RPF who are intolerant or refractory to steroid single therapy, MTX may be considered as useful and safe second-line treatment
Serum free light chains in the differential diagnosis and prognosis of primary and secondary hypogammaglobulinemia: To the editor
No full textVenom immunotherapy during COVID-19 pandemic: Experience from a University Allergy Center in Northern Italy
Full text linkDuring the ongoing pandemic of Coronavirus Disease 2019 (COVID-19) allergic patients need to continue their constant and proper treatment, including allergen-specific immunotherapy. These patients are expected to be at a higher risk for exacerbation of lung inflammation during viral infection. We investigated the putative interplay existing between allergen-specific immunotherapy and COVID-19 infection in a Hymenoptera venom-allergic population. We evaluated the frequency and severity of COVID-19 infection in a cohort of 211 subjects referring to our center for the regular administration of venom immunotherapy (VIT). Our result showed that the median age of our cohort is similar to the one that in our region has been associated with a high incidence of COVID-19 infection, increased hospitalization, and mortality rates. We reported only an isolated positivity of COVID-19 in the overall group; whereas none suffered from upper airway symptoms associated with COVID-19 (fever, cough, dyspnoea, sore throat, anosmia, and/or ageusia). Even though the demographic characteristics pose a substantial risk for such a population, we suggest that a regular administration of VIT may help in the development of an immunological milieu able to down modulate the Th1/Th17 environment that has been linked to inflammatory manifestations of COVID-19. To the best of our knowledge, this is the first description of the incidence of COVID-19 infection in Hymenoptera venom allergic patients treated with VIT, suggesting indirectly that venom immune tolerance-inducing treatment may be capable of reducing the aberrant inflammatory response induced by the virus in this specific population
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