[Clinically amyopathic dermatomyositis : a rare entity associated with acute and severe interstitial lung disease]. / La dermatomyosite amyopathique : une entité rare associée à une pneumopathie interstitielle fulminante.

Dermatomyositis is a rare disease of unknown etiology characterized by a severe inflammatory myopathy associated with a cutaneous syndrome. Dermatomyositis is associated with multisystemic disorders mostly represented by cardiac, pulmonary and articular involvements, which are particularly associated with a bad prognosis. We report a case of a 50-year-old patient suffering from dermatomyositis associated with an interstitial lung disease with a particularly fast and pejorative clinical evolution. The anti-Melanoma Differentiation-Associated gene 5 (anti-MDA5) antibodies are frequently associated with a severe and rapidly progressive lung disease without myositis named «amyopathic dermatomyositis¼. High blood levels of anti-MDA5 were found in our patient. Despite maximal immunosuppressive treatment and supportive care, he died 3 months after the diagnosis. Patients may present different antibodies that correspond to distinct clinical phenotypes of dermatomyositis. The anti-MDA5 is known to be a marker of clinically amyopathic dermatomyositis (CADM) associated with a rapidly progressive interstitial lung disease. Moreover, blood level of anti-MDA5 antibody predicts the response to treatment and survival in CADM.

La dermatomyosite est une maladie rare, d'étiologie inconnue, caractérisée par une myopathie inflammatoire associée à un syndrome cutané typique. Outre l'atteinte musculaire et cutanée, la dermatomyosite peut se manifester par des atteintes organiques, notamment pulmonaires, cardiaques et articulaires qui contribuent à la sévérité de la maladie. Nous rapportons le cas d'un patient âgé de 50 ans atteint d'une dermatomyosite compliquée d'une pneumopathie interstitielle d'évolution clinique particulièrement rapide et péjorative. Le patient présentait des anticorps anti-MDA5 (anti-Melanoma Differentiation-Associated gene 5), anticorps associés assez fréquemment à une atteinte pulmonaire sévère et rapidement progressive, ainsi qu'à une présentation particulière de la maladie appelée «dermatomyosite amyopathique¼. Malgré un traitement immunosuppresseur intensif, l'état pulmonaire du patient s'est rapidement aggravé, entraînant son décès par insuffisance respiratoire trois mois après le diagnostic. Cette histoire clinique illustre le fait que les patients atteints de dermatomyosite peuvent présenter différents anticorps qui correspondent à des phénotypes cliniques distincts. L'association entre anticorps anti-MDA5 et la pathologie pulmonaire interstitielle justifie qu'un screening des anticorps anti-MDA5 soit réalisé chez les patients porteurs d'une dermatomyosite. De plus, le titrage sanguin des anti-MDA5 est un facteur pronostique de la réponse au traitement et de la survie.

Investigating the rationale for COPD maintenance therapy prescription across Europe, findings from a multi-country study.

This study aims to understand healthcare professionals' thoughts and motivations about optimal management and treatment of patients with chronic obstructive pulmonary disease (COPD). We conducted a DELPHI survey through an online questionnaire distributed to 220 panellists from six European countries and a discrete choice experiment to describe the relationship between selected clinical criteria and the initial COPD treatment of choice. One hundred twenty-seven panellists (general practitioners [GPs] and pulmonologists) completed the survey. Despite the familiarity and use (89.8%) of the GOLD classification for initial treatment selection, a frequent use of LAMA/LABA/ICS was noted. In fact, panellists agreed that inhaled corticosteroids (ICS) are over-prescribed in the primary care setting. Our study showed that GPs felt less confident than pulmonologists with ICS withdrawal. This mismatch observed between best practice and behaviour indicates the need to increase awareness and efforts to improve the adherence to guidelines in clinical practice.

Ly6Chi monocytes balance regulatory and cytotoxic CD4 T cell responses to control virus-induced immunopathology.

Gammaherpesviruses (γHVs) have coevolved with their host, leading to a remarkably high infection prevalence and establishment of latency. The lifelong persistence of γHVs in hosts appears to broadly shape host immunity, and we show here that pulmonary infection with Murid herpesvirus 4 (MuHV-4), a mouse γHV, drives the recruitment of Ly6Chi monocytes (MOs) into the airway, thereby modulating the host immune response. The absence of Ly6Chi MOs is associated with severe virus-induced immunopathology and the systemic release of inflammatory mediators. Mechanistically, MuHV-4-imprinted MOs recruit CD4 T cells to the airways and trigger immunosuppressive signaling pathways through the PD-L1/PD-1 axis, thereby dampening the deleterious activation of cytotoxic CD4 T cells. These results uncover a role for Ly6Chi MOs in modulating CD4 T cell functions and reveal pathways that could be targeted therapeutically to reduce detrimental immunopathological responses associated with respiratory viral infections.

Local nebulization of 1α,25(OH)2D3 attenuates LPS-induced acute lung inflammation.

BACKGROUND: Evidence supports a critical role of vitamin D status on exacerbation in chronic obstructive pulmonary disease, indicating the need to avoid vitamin D deficiency in these patients. However, oral vitamin D supplementation is limited by the potential risk for hypercalcemia. In this study, we investigated if local delivery of vitamin D to the lungs improves vitamin D-mediated anti-inflammatory action in response to acute inflammation without inducing hypercalcemia. METHODS: We studied vitamin D sufficient (VDS) or deficient (VDD) mice in whom 1α,25(OH)2D3 (0.2 µg/kg) or a vehicle followed by lipopolysaccharide (LPS 25 µg) were delivered to the lung as a micro-spray. RESULTS: Local 1α,25(OH)2D3 reduced LPS-induced inflammatory cells in bronchoalveolar lavage (BAL) in VDS (absolute number of cells: - 57% and neutrophils - 51% p < 0.01) and tended to diminish LPS-increased CXCL5 BAL levels in VDS (- 40%, p = 0.05) while it had no effect on CXCL1 and CXCL2 in BAL and mRNA in lung of VDS and VDD. It also significantly attenuated the increased IL-13 in BAL and lung, especially in VDD mice (- 41 and - 75%, respectively). mRNA expression of Claudin-18 in lung was significantly lower in VDS mice with local 1α,25(OH)2D3 while Claudin-3, -5 and -8 mRNA levels remained unchanged. Finally, in VDD mice only, LPS reduced lung mRNA expression of adhesion junction Zona-occludens-1, in addition to increasing uric acid and total protein in BAL, which both were prevented by local 1α,25(OH)2D3. CONCLUSION: Under normal levels of vitamin D, local 1α,25(OH)2D3 nebulization into the lung efficiently reduced LPS induction of inflammatory cells in BAL and slightly attenuated LPS-increase in CXCL5. In case of severe vitamin D deficiency, although local 1α,25(OH)2D3 nebulization failed to significantly minimize cellular inflammation in BAL at this dose, it prevented epithelial barrier leakage and damage in lung. Additional research is needed to determine the potential long-term beneficial effects of local 1α,25(OH)2D3 nebulization on lung inflammation.

How to Choose the Right Inhaler Using a Patient-Centric Approach?

There are many different inhaler devices and medications on the market for the treatment of asthma and chronic obstructive pulmonary disease, with over 230 drug-delivery system combinations available. However, despite the abundance of effective treatment options, the achieved disease control in clinical practice often remains unsatisfactory. In this context, a key determining factor is the match or mismatch of an inhalation device with the characteristics or needs of an individual patient. Indeed, to date, no ideal device exists that fits all patients, and a personalized approach needs to be considered. Several useful choice-guiding algorithms have been developed in the recent years to improve inhaler-patient matching, but a comprehensive tool that translates the multifactorial complexity of inhalation therapy into a user-friendly algorithm is still lacking. To address this, a multidisciplinary expert panel has developed an evidence-based practical treatment tool that allows a straightforward way of choosing the right inhaler for each patient.

Role for the metalloproteinase ADAM28 in the control of airway inflammation, remodelling and responsiveness in asthma.

Background: Asthma is characterized by morphological modifications of the airways (inflammation and remodelling) and bronchial hyperresponsiveness. Mechanisms linking these two key features of asthma are still poorly understood. ADAM28 (a disintegrin and metalloproteinase 28) might play a role in asthma pathophysiology. ADAM28 exists as membrane-bound and soluble forms and is mainly expressed by lymphocytes and epithelial cells. Methods: ADAM28-/- mice and ADAM28+/+ counterparts were sensitized and exposed to ovalbumin (OVA). Airway responsiveness was measured using the flexiVent® system. After sacrifice, bronchoalveolar lavage (BAL) was performed and lungs were collected for analysis of airway inflammation and remodelling. Results: The expression of the soluble form of ADAM28 was lower in the lungs of OVA-exposed mice (as compared to PBS-exposed mice) and progressively increased in correlation with the duration of allergen exposure. In lungs of ADAM28-/- mice exposed to allergens, the proportion of Th2 cells among CD 4 + cells and the number of B cells were decreased. Bronchial responsiveness was lower in ADAM28-/- mice exposed to allergens and similar to the responsiveness of sham-challenged mice. Similarly, features of airway remodelling (collagen deposition, smooth muscle hyperplasia, mucous hyperplasia) were significantly less developed in OVA-exposed ADAM28-/- animals in sharp contrasts to ADAM28+/+. In addition, we report the first evidence of ADAM28 RNA expression by lung fibroblasts and we unveil a decreased capacity of lung fibroblasts extracted from OVA-exposed ADAM28-/- mice to proliferate as compared to those extracted from OVA-exposed ADAM28+/+ suggesting a direct contribution of this enzyme to the modulation of airway remodelling. Conclusion: These results suggest that ADAM28 might be a key contributor to the pathophysiology of asthma.

Severe asthma: oral corticosteroid alternatives and the need for optimal referral pathways.

OBJECTIVE: Patients with severe asthma require high-dose inhaled corticosteroids, with or without add-on treatments, to maintain asthma control. Because symptom control remains unsatisfactory in some patients despite these therapies, maintenance therapy with oral corticosteroids (OCS) remains considered a treatment option by physicians. Besides physician-diagnosed exacerbations, many patients intermittently self-medicate with OCS during episodes of worsening symptoms or as a prevention of such episodes. However, long-term OCS use is associated with several comorbidities that may decrease health-related quality of life, worsen prognosis, and should ideally require monitoring and management. In this review, we discuss the adverse effects of OCS use, the OCS-sparing effect of biologics in severe asthma, and the need for optimal referral pathways to ensure the best outcomes for those at-risk asthma patients. DATA SOURCES: PubMed. STUDY SELECTION: Studies with results on the OCS-sparing effect of biologics in adult severe asthma were selected. RESULTS: Chronic and intermittent OCS use in asthma is associated with considerable adverse effects in asthma. Omalizumab, mepolizumab, benralizumab, and dupilumab reduce the need for OCS in severe asthma, while also reducing the exacerbation rate and improving several patient-related outcomes. CONCLUSION: Targeted biologic therapies have revolutionized the treatment of uncontrolled severe asthma by reducing or even eliminating the need for OCS and improving other major outcomes. Novel agents are now rapidly increasing the therapeutic armamentarium, but additional efforts are needed to optimize referral pathways in order to ensure sustainable access to these therapies.

The Budesonide-Hydroxypropyl-ß-Cyclodextrin Complex Attenuates ROS Generation, IL-8 Release and Cell Death Induced by Oxidant and Inflammatory Stress. Study on A549 and A-THP-1 Cells.

Synthetic glucocorticoids such as budesonide (BUD) are potent anti-inflammatory drugs commonly used to treat patients suffering from chronic inflammatory diseases. A previous animal study reported a higher anti-inflammatory activity with a 2-hydroxypropyl-ß-cyclodextrin (HPßCD)-based formulation of BUD (BUD:HPßCD). This study investigated, on cellular models (A549 and A-THP-1), the effect of BUD:HPßD in comparison with BUD and HPßCD on the effects induced by oxidative and inflammatory stress as well as the role of cholesterol. We demonstrated the protective effect afforded by BUD:HPßCD against cytotoxicity and ROS generation induced by oxidative and inflammatory stress. The effect observed for BUD:HPßCD was comparable to that observed with HPßCD with no major effect of cholesterol content. We also demonstrated (i) the involvement of the canonical molecular pathway including ROS generation, a decrease in PI3K/Akt activation, and decrease in phosphorylated/unphosphorylated HDAC2 in the effect induced by BUD:HPßCD, (ii) the maintenance of IL-8 decrease with BUD:HPßCD, and (iii) the absence of improvement in glucocorticoid insensitivity with BUD:HPßCD in comparison with BUD, in conditions where HDAC2 was inhibited. Resulting from HPßCD antioxidant and anticytotoxic potential and protective capacity against ROS-induced PI3K/Akt signaling and HDAC2 inhibition, BUD:HPßCD might be more beneficial than BUD alone in a context of concomitant oxidative and inflammatory stress.

Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19.

Infection with SARS-CoV-2 is causing a deadly and pandemic disease called coronavirus disease-19 (COVID-19). While SARS-CoV-2-triggered hyperinflammatory tissue-damaging and immunothrombotic responses are thought to be major causes of respiratory failure and death, how they relate to lung immunopathological changes remains unclear. Neutrophil extracellular traps (NETs) can contribute to inflammation-associated lung damage, thrombosis, and fibrosis. However, whether NETs infiltrate particular compartments in severe COVID-19 lungs remains to be clarified. Here we analyzed postmortem lung specimens from four patients who succumbed to COVID-19 and four patients who died from a COVID-19-unrelated cause. We report the presence of NETs in the lungs of each COVID-19 patient. NETs were found in the airway compartment and neutrophil-rich inflammatory areas of the interstitium, while NET-prone primed neutrophils were present in arteriolar microthrombi. Our results support the hypothesis that NETs may represent drivers of severe pulmonary complications of COVID-19 and suggest that NET-targeting approaches could be considered for the treatment of uncontrolled tissue-damaging and thrombotic responses in COVID-19.

ADAM28: Another ambivalent protease in cancer.

Emergence of novel therapeutic options in a perspective of personalized therapy of cancer relies on the discovery of precise molecular mechanisms involved in the switch from a localized tumor to invasive metastasis spread. Pro-tumor functions have been mostly ascribed to proteolytic enzymes from the metalloproteinase family including A Disintegrin And Metalloproteinases (ADAMs). Particularly, when expressed by cancer cells, ADAM28 protease supports cancer cell proliferation, survival and migration as well as metastatic progression. In sharp contrast, ADAM28 derived from the tumor microenvironment has shown to exert strong protective effects against deleterious metastasis dissemination. Indeed, depletion of host-derived ADAM28 (ADAM28 KO mice) accelerates colonization lung tissues, increases tumor foci implantation, and impairs T cell immune response. In this review, we outline specific ADAM28 functions when specifically expressed by carcinoma cells or by tumor microenvironment. Finally, we discuss about future research strategies that could be pursued to highlight new functions of this protease in cancer.

Maternal asthma is associated with persistent changes in allergic offspring antibody glycosylation.

BACKGROUND: Maternal asthma during pregnancy is considered an environmental risk factor for asthma development in children. Immunoglobulin G (IgG) antibodies that are transferred from the mother to the fetus are known to act in a pro- or anti-inflammatory manner depending on their glycosylation status. OBJECTIVE: Using a mouse model, we examined how maternal allergic airway inflammation during pregnancy influenced offspring experimental asthma severity, as well as maternal and offspring serum IgG antibody glycosylation patterns. Additionally, the effects of maternal and offspring exposure to the same or different allergens were investigated. METHODS: Female mice were either sham sensitized or sensitized to casein (CAS) or ovalbumin (OVA) before mating. Subsequently, allergic lung inflammation was induced in pregnant dams via aerosol allergen challenge (sham, CAS or OVA). After weaning, pups were subjected to an experimental asthma protocol using OVA. Asn-297 IgG glycosylation was analysed in maternal and offspring serum. RESULTS: When mothers and offspring were sensitized to the same allergen (OVA-OVA), offspring had more severe experimental asthma. This was evidenced by altered antibody concentrations, increased bronchoalveolar lavage inflammatory cell influx and decreased lung tissue and lung draining lymph node regulatory T cell percentages. When mothers and offspring were sensitized to different allergens (CAS-OVA), this phenotype was no longer observed. Additionally, maternal serum from allergic mothers had significantly higher levels of pro-inflammatory IgG1, shown by decreased galactosylation and sialylation at the Asn-297 glycosylation site. Similar glycosylation patterns were observed in the serum of adult allergic offspring from allergic mothers. CONCLUSIONS AND CLINICAL RELEVANCE: We observed a strong association between maternal experimental asthma during pregnancy, increased offspring airway inflammation and pro-inflammatory IgG glycosylation patterns in mothers and offspring. IgG glycosylation is not a standard measurement in the clinical setting, and we argue that it may be an important parameter to include in future clinical studies.

Locally instructed CXCR4hi neutrophils trigger environment-driven allergic asthma through the release of neutrophil extracellular traps.

Low exposure to microbial products, respiratory viral infections and air pollution are major risk factors for allergic asthma, yet the mechanistic links between such conditions and host susceptibility to type 2 allergic disorders remain unclear. Through the use of single-cell RNA sequencing, we characterized lung neutrophils in mice exposed to a pro-allergic low dose of lipopolysaccharide (LPS) or a protective high dose of LPS before exposure to house dust mites. Unlike exposure to a high dose of LPS, exposure to a low dose of LPS instructed recruited neutrophils to upregulate their expression of the chemokine receptor CXCR4 and to release neutrophil extracellular traps. Low-dose LPS-induced neutrophils and neutrophil extracellular traps potentiated the uptake of house dust mites by CD11b+Ly-6C+ dendritic cells and type 2 allergic airway inflammation in response to house dust mites. Neutrophil extracellular traps derived from CXCR4hi neutrophils were also needed to mediate allergic asthma triggered by infection with influenza virus or exposure to ozone. Our study indicates that apparently unrelated environmental risk factors can shape recruited lung neutrophils to promote the initiation of allergic asthma.

Preclinical evaluation of topically-administered PEGylated Fab' lung toxicity.

PEGylation is a promising approach to increase the residence time of antibody fragments in the lungs and sustain their therapeutic effects. However, concerns arise as to the potential pulmonary toxicity of antibody fragments conjugated to high molecular weight (HMW) polyethylene glycol (PEG), notably after repeated administrations, and the possibility of PEG accumulation in the lungs. The purpose of this proof-of-concept study is to give insights about the safety of lung administration of a Fab' anti-IL17A antibody fragment conjugated to two-armed 40 kDa PEG (PEG40). The presence of the PEG40 moiety inside alveolar macrophages remained stable for at least 24 h after intratracheal administration of PEG40-Fab' to mice. PEG40 was then progressively cleared from alveolar macrophages. Incubation of PEG40 alone with macrophages in vitro did not significantly harm macrophages and did not affect phagocytosis or the production of inflammatory markers. After acute or chronic administration of PEG40-Fab' to mice, no signs of significant pulmonary toxicity or inflammatory cell accumulation were observed. A vacuolization of alveolar macrophages not associated with any inflammation was noticed when PEG40, PEG40-Fab', or unPEGylated Fab' were administered. To conclude this preliminary proof of concept study, acute or repeated pulmonary administrations of PEGylated Fab' appear safe in rodents.

Stromal integrin α11 regulates PDGFR-ß signaling and promotes breast cancer progression.

Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors such as breast cancer (BC). Herein, we identify an integrin α11/PDGFRß+ CAF subset displaying tumor-promoting features in BC. In the preclinical MMTV-PyMT mouse model, integrin α11-deficiency led to a drastic reduction of tumor progression and metastasis. A clear association between integrin α11 and PDGFRß was found at both transcriptional and histological levels in BC specimens. High stromal integrin α11/PDGFRß expression was associated with high grades and poorer clinical outcome in human BC patients. Functional assays using five CAF subpopulations (one murine, four human) revealed that integrin α11 promotes CAF invasion and CAF-induced tumor cell invasion upon PDGF-BB stimulation. Mechanistically, integrin α11 pro-invasive activity relies on its ability to interact with PDGFRß in a ligand-dependent manner and to promote its downstream JNK activation, leading to the production of tenascin C, a pro-invasive matricellular protein. Pharmacological inhibition of PDGFRß and JNK impaired tumor cell invasion induced by integrin α11-positive CAFs. Collectively, our study uncovers an integrin α11-positive subset of pro-tumoral CAFs that exploits PDGFRß/JNK signalling axis to promote tumor invasiveness in BC.

Relationship between peak expiratory flow and incidence of frailty, deaths and falls among nursing home residents: Results of the SENIOR cohort.

OBJECTIVE: To correlate peak expiratory flow (PEF) with the incidence of frailty, deaths and falls among nursing home residents. METHODS: This is a 1-year longitudinal analysis performed on the clinical data of the SENIOR cohort. PEF, measured by peak flow meter, was considered as "low" when the observed value was ≤80% of the theoretical value. Physical capacity was evaluated using Short Physical Performance Battery, balance and gait using Tinetti test and muscle strength using a dynamometer. The incidence of frailty was defined as the transition from a "robust" or "prefrail" status to a "frail" status following Fried's criteria. Deaths and falls were also collected. RESULTS: Among 646 subjects included at baseline (83.2 ± 9 years and 72.1% women), 297 (45.7%) displayed a low PEF. In this subgroup, physical capacity (p-values from 0.01 to <0.001), muscle strength (p < 0.001), balance and gait score (p < 0.001) were significantly lower compared to subjects displaying normal PEF. Subjects who became frail after one year displayed a lower % of the theoretical PEF value compared to those that did not (88.52 ± 45.06 vs 102.78 ± 50.29, respectively, p = 0.03). After adjustment for potential confounding variables (calf circumference, Tinetti test, SPPB test and handgrip strength), PEF was no longer associated with the occurrence of frailty. There was no association between PEF and mortality and falls. CONCLUSION: In a nursing home setting, PEF is not an independent factor associated with the incidence of frailty, deaths and falls.

Ozone-primed neutrophils promote early steps of tumour cell metastasis to lungs by enhancing their NET production.

BACKGROUND: Air pollution, including particulates and gazes such as ozone (O3), is detrimental for patient's health and has repeatedly been correlated to increased morbidity and mortality in industrialised countries. Although studies have described a link between ambient particulate matter and increased lung cancer morbidity, no direct relation has yet been established between O3 exposure and metastatic dissemination to lungs. OBJECTIVES: To outline the mechanisms through which pulmonary O3 exposure modulates metastasis kinetics in an experimental mouse model of O3 exposure. METHODS: Metastatic responses to pulmonary O3 exposure were assessed using a reliable experimental mouse model of concomitant pulmonary O3 exposure and tumour cell injection. Roles of neutrophils in O3-induced lung metastasis were highlighted using blocking anti-Ly6G antibodies; moreover, the implication of neutrophil extracellular traps (NETs) in metastatic processes was evaluated using MRP8cre-Pad4lox/lox mice or by treating mice with DNase I. RESULTS: Pulmonary O3 exposure strongly facilitates the establishment of lung metastasis by (1) Inducing a pulmonary injury and neutrophilic inflammation, (2) Influencing very early steps of metastasis, (3) Priming neutrophils' phenotype to release NETs that favour tumour cell colonisation in lungs. The ability of O3-primed neutrophils to enhance lung colonisation by tumour cells was proven after their adoptive transfer in Balb/c mice unexposed to O3. CONCLUSIONS: Pulmonary neutrophils induced by O3 promote metastatic dissemination to lungs by producing NETs. These findings open new perspectives to improve treatment and prevention strategies in patients affected by metastatic diseases.