Background: Macrophages are pivotal cells in sarcoidosis. Monocytes-derived (MD) macrophages have recently been demonstrated to play a major role especially in pulmonary sarcoidosis. From inflammatory tissues to granulomas, they may be exposed to low oxygen tension environments. As hypoxia impact on sarcoidosis immune cells has never been addressed, we designed the present study to investigate MD-macrophages from sarcoidosis patients in this context. We hypothesized that hypoxia may induce functional changes on MD-macrophages which could have a potential impact on the course of sarcoidosis.Methods: We studied MD-macrophages, from high active sarcoidosis (AS) (n=26), low active or inactive sarcoidosis (IS) (n=24) and healthy controls (n=34) exposed 24 hours to normoxia (21% O₂) or hypoxia (1.5% O₂). Different macrophage functions were explored: hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-κB) activation, cytokines secretion, phagocytosis, CD80/CD86/HLA-DR expression, profibrotic response.Results: We observed that hypoxia, with a significantly more pronounced effect in AS compared with controls and IS, increased the HIF-1α trans-activity, promoted a proinflammatory response (TNFα, IL1ß) without activating NF-κB pathway and a profibrotic response (TGFß1, PDGF-BB) with PAI-1 secretion associated with human lung fibroblast migration inhibition. These results were confirmed by immunodetection of HIF-1α and PAI-1 in granulomas observed in pulmonary biopsies from patients with sarcoidosis. Hypoxia also decreased the expression of CD80/CD86 and HLA-DR on MD-macrophages in the three groups while it did not impair phagocytosis and the expression of CD36 expression on cells in AS and IS at variance with controls.Conclusions: Hypoxia had a significant impact on MD-macrophages from sarcoidosis patients, with the strongest effect seen in patients with high active disease. Therefore, hypoxia could play a significant role in sarcoidosis pathogenesis by increasing the macrophage proinflammatory response, maintaining phagocytosis and reducing antigen presentation, leading to a deficient T cell response. In addition, hypoxia could favor fibrosis by promoting profibrotic cytokines response and by sequestering fibroblasts in the vicinity of granulomas.

Pulmonary function is tightly linked to the lung mechanical behavior, especially large deformation during breathing. Interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF), have an impact on the pulmonary mechanics and consequently alter lung function. However, IPF remains poorly understood, poorly diagnosed, and poorly treated. Currently, the mechanical impact of such diseases is assessed by pressure–volume curves, giving only global information. We developed a poromechanical model of the lung that can be personalized to a patient based on routine clinical data. The personalization pipeline uses clinical data, mainly computed tomography (CT) images at two time steps and involves the formulation of an inverse problem to estimate regional compliances. The estimation problem can be formulated both in terms of “effective”, i.e., without considering the mixture porosity, or “rescaled,” i.e., where the first-order effect of the porosity has been taken into account, compliances. Regional compliances are estimated for one control subject and three IPF patients, allowing to quantify the IPF-induced tissue stiffening. This personalized model could be used in the clinic as an objective and quantitative tool for IPF diagnosis.

Sarcoidosis is a systemic disease characterised by non-necrotic epithelioid granulomas that preferentially involve the respiratory tract [1]. In pulmonary sarcoidosis, granulomas develop throughout the lung parenchyma, notably in the perivascular and peribronchiolar interstitial spaces, as well as in the walls of small pulmonary arteries and veins [2]. This vascular involvement defines sarcoid vasculitis, which was classified among the vasculitides associated with systemic diseases at the 2012 Chapel Hill consensus conference [3]. Pulmonary hypertension is a major complication that occurs in 5% of patients with sarcoidosis and may cause death or require lung transplantation [4–6].

We read with great interest the study recently published in the European Respiratory Journal from Ravaglia et al. [1] entitled “Clinical, radiological and pathological findings in patients with persistent lung disease following SARS-CoV-2 infection”. As this study and others point out, lung endothelium [2], from proximal to distal parts, is a well-known target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the acute phase of the infection [3] and leads to a persisting vascular remodelling [1, 4]. Exploring lung vascular remodelling in post-acute coronavirus disease 2019 (COVID-19) patients using noninvasive tools is one of the post-epidemic challenges that physicians have to face. Contrast computed tomography (CT) scanning and lung perfusion technetium-99m (^99mTc)-macroaggregated albumin scintigraphy (SPECT-CT) are routine tools used to explore the lung vascular compartment, and are primarily used to rule out chronic or distal pulmonary embolism in suspected pulmonary hypertension [5]. However, the large number of patients infected, the need to inject either a contrast agent or a radionuclide and the cost of these exams limit their application to investigate post-acute COVID-19 lung vascular remodelling. Recently, we have developed computerised image processing from routine high-resolution noncontrast computed tomography (HRCT) scans for the identification and characterisation of vascular pruning via small-branch pruning of pulmonary arteries under various conditions [6]. Therefore, we question whether such a computational analysis on a routinely performed HRCT scan would allow the study of a possible vascular remodelling after COVID-19 infection. In this preliminary study, we established a method for computerising SPECT-CT to obtain quantitative data and compared them with those obtained from HRCT scans in the same patients.