Thomas Gille

Imaging of sarcoidosis of the airways and lung parenchyma and correlation with lung function

Imaging has a prominent role in the assessment of sarcoidosis diagnosis and outcome, which are extremely variable. Chest radiography staging helps predict the probability of spontaneous remission, and stage IV is associated with higher mortality. However, the reproducibility of reading is poor and changes in radiography and lung function are inconsistently correlated, which may be problematic for the monitoring of disease and treatment response. Chest computed tomography (CT) makes a great diagnostic contribution in difficult cases. Bilateral hilar lymphadenopathy with peri-lymphatic micronodular pattern is highly specific for sarcoidosis. CT is important for the investigation of pulmonary complications, including aspergilloma and pulmonary hypertension. CT improves the yield of bronchoscopy for obtaining a positive endobronchial or transbronchial biopsy. CT findings may also discriminate between active inflammation and irreversible fibrosis, with occasional influence on therapeutic decisions. Three CT patterns of fibrotic sarcoidosis are identified, with different functional profiles: predominant bronchial distortion is associated with obstruction; honeycombing is associated with restriction and lower diffusing capacity of the lung for carbon monoxide; whereas functional impairment is relatively minor with linear pattern. The clinical impact of correlations between CT severity scores and functional impairment is uncertain, except for its utility elucidating the mechanisms of airflow limitation, which include bronchial distortion, peribronchovascular thickening, air-trapping and bronchial compression by lymphadenopathy.

Conditioned media from mesenchymal stromal cells restore sodium transport and preserve epithelial permeability in an in vitro model of acute alveolar injury

Mesenchymal stromal cells (MSCs) or their media (MSC-M) were reported to reverse acute lung injury (ALI)-induced decrease of alveolar fluid clearance. To determine the mechanisms by which MSC-M exert their beneficial effects, an in vitro model of alveolar epithelial injury was created by exposing primary rat alveolar epithelial cells (AECs) to hypoxia (3% O2) plus cytomix, a combination of IL-1β, TNF-α, and IFN-γ. MSC-M were collected from human MSCs exposed for 12 h to either normoxia (MSC-M) or to hypoxia plus cytomix (HCYT-MSC-M). This latter condition was used to model the effect of alveolar inflammation and hypoxia on paracrine secretion of MSCs in the injured lung. Comparison of paracrine soluble factors in MSC media showed that the IL-1 receptor antagonist and prostaglandin E2 were markedly increased while keratinocyte growth factor (KGF) was twofold lower in HCYT-MSC-M compared with MSC-M. In AECs, hypoxia plus cytomix increased protein permeability, reduced amiloride-sensitive short-circuit current (AS-Isc), and also decreased the number of α-epithelial sodium channel (α-ENaC) subunits in the apical membrane. To test the effects of MSC media, MSC-M and HCYT-MSC-M were added for an additional 12 h to AECs exposed to hypoxia plus cytomix. MSC-M and HCYT-MSC-M completely restored epithelial permeability to normal. MSC-M, but not HCYT-MSC-M, significantly prevented the hypoxia plus cytomix-induced decrease of ENaC activity and restored apical α-ENaC channels. Interestingly, KGF-deprived MSC-M were unable to restore amiloride-sensitive sodium transport, indicating a possible role for KGF in the beneficial effect of MSC-M. These results indicate that MSC-M may be a preferable therapeutic option for ALI.

Hypoxia-Induced Inhibition of Epithelial Na+ Channels in the Lung. Role of Nedd4-2 and the Ubiquitin-Proteasome Pathway

Transepithelial sodium transport via alveolar epithelial Na(+) channels (ENaC) and Na(+),K(+)-ATPase constitutes the driving force for removal of alveolar edema fluid. Alveolar hypoxia associated with pulmonary edema may impair ENaC activity and alveolar Na(+) absorption through a decrease of ENaC subunit expression at the apical membrane of alveolar epithelial cells (AECs). Here, we investigated the mechanism(s) involved in this process in vivo in the β-Liddle mouse strain mice carrying a truncation of β-ENaC C-terminus abolishing the interaction between β-ENaC and the ubiquitin protein-ligase Nedd4-2 that targets the channel for endocytosis and degradation and in vitro in rat AECs. Hypoxia (8% O2 for 24 h) reduced amiloride-sensitive alveolar fluid clearance by 69% in wild-type mice but had no effect in homozygous mutated β-Liddle littermates. In vitro, acute exposure of AECs to hypoxia (0.5-3% O2 for 1-6 h) rapidly decreased transepithelial Na(+) transport as assessed by equivalent short-circuit current Ieq and the amiloride-sensitive component of Na(+) current across the apical membrane, reflecting ENaC activity. Hypoxia induced a decrease of ENaC subunit expression in the apical membrane of AECs with no change in intracellular expression and induced a 2-fold increase in α-ENaC polyubiquitination. Hypoxic inhibition of amiloride-sensitive Ieq was fully prevented by preincubation with the proteasome inhibitors MG132 and lactacystin or with the antioxidant N-acetyl-cysteine. Our data strongly suggest that Nedd4-2-mediated ubiquitination of ENaC leading to endocytosis and degradation of apical Na(+) channels is a key feature of hypoxia-induced inhibition of transepithelial alveolar Na(+) transport.

Mesenchymal stem cells protect from hypoxia-induced alveolar epithelial-mesenchymal transition.

Administration of bone marrow-derived human mesenchymal stem cells (hMSC) reduces lung inflammation, fibrosis, and mortality in animal models of lung injury, by a mechanism not completely understood. We investigated whether hMSC would prevent epithelial-mesenchymal transition (EMT) induced by hypoxia in primary rat alveolar epithelial cell (AEC). In AEC cultured on semipermeable filters, prolonged hypoxic exposure (1.5% O2 for up to 12 days) induced phenotypic changes consistent with EMT, i.e., a change in cell morphology, a decrease in transepithelial resistance (Rte) and in the expression of epithelial markers [zonula occludens-1 (ZO-1), E-cadherin, AQP-5, TTF-1], together with an increase in mesenchymal markers [vimentin, α-smooth muscle actin (α-SMA)]. Expression of transcription factors driving EMT such as SNAIL1, ZEB1, and TWIST1 increased after 2, 24, and 48 h of hypoxia, respectively. Hypoxia also induced TGF-β1 mRNA expression and the secretion of active TGF-β1 in apical medium, and the expression of connective tissue growth factor (CTGF), two inducers of EMT. Coculture of AEC with hMSC partially prevented the decrease in Rte and in ZO-1, E-cadherin, and TTF-1 expression, and the increase in vimentin expression induced by hypoxia. It also abolished the increase in TGF-β1 expression and in TGF-β1-induced genes ZEB1, TWIST1, and CTGF. Finally, incubation with human recombinant KGF at a concentration similar to what was measured in hMSC-conditioned media restored the expression of TTF-1 and prevented the increase in TWIST1, TGF-β1, and CTGF in hypoxic AEC. Our results indicate that hMSC prevent hypoxia-induced alveolar EMT through the paracrine modulation of EMT signaling pathways and suggest that this effect is partly mediated by KGF.

Adult Onset Asthma and Periocular Xanthogranuloma (AAPOX), a Rare Entity With a Strong Link to IgG4-Related Disease: An Observational Case Report Study.

AbstractAdult onset asthma and periocular xanthogranuloma (AAPOX) is a rare non-Langerhans histiocytosis characterized histopathologically by a periocular infiltration of foamy histiocytes and Touton giant cells. Benign hyperplasia with plasma cell infiltration is classically described in eyelids or lymph nodes of AAPOX patients. It is also a characteristic feature of IgG4-related disease (IgG4-RD), a new entity defined by an IgG4-bearing plasma cell infiltration of organs.To determine if AAPOX syndrome shares clinical, biological, and histopathological characteristics with IgG4-RD, we used the comprehensive clinical diagnostic criteria for IgG4-RD in a retrospective case series of three consecutive patients with histologically-proven AAPOX. Patients who were diagnosed with AAPOX at a French academic referral center for orbital inflammation between November 1996 and March 2013 were enrolled. Biopsies from ocular adnexa or other organs were systematically reexamined. For each patient, clinical and serological data, radiologic findings, and treatment were retrospectively analyzed.Two AAPOX patients fulfilled all of the diagnostic criteria for a definite IgG4-RD. One patient who lacked the serological criteria fulfilled the criteria of a probable IgG4-RD.These 3 cases of AAPOX patients fulfilled the IgG4-RD comprehensive clinical diagnostic criteria. To our knowledge, this is the first observational case report study to clearly show a strong relationship between IgG4-RD and AAPOX syndrome.

Hypoxia inhibits semicarbazide-sensitive amine oxidase activity in adipocytes.

Semicarbazide-sensitive amine oxidase (SSAO), an enzyme highly expressed on adipocyte plasma membranes, converts primary amines into aldehydes, ammonium and hydrogen peroxide, and is likely involved in endothelial damage during the course of diabetes and obesity. We investigated whether in vitro, adipocyte SSAO was modulated under hypoxic conditions that is present in adipose tissue from obese or intensive care unit. Physical or pharmacological hypoxia decreased SSAO activity in murine adipocytes and human adipose tissue explants, while enzyme expression was preserved. This effect was time-, dose-dependent and reversible. This down-regulation was confirmed in vivo in subcutaneous adipose tissue from a rat model of hypoxia. Hypoxia-induced suppression in SSAO activity was independent of the HIF-1-α pathway or of oxidative stress, but was partially antagonized by medium acidification. Hypoxia-induced down-regulation of SSAO activity could represent an adaptive mechanism to lower toxic molecules production, and may thus protect from tissue injury during these harmful conditions.

Chronic beryllium disease: azathioprine as a possible alternative to corticosteroid treatment

To the Editor: Chronic beryllium disease (CBD) is a chronic granulomatous disease that mainly affects the lungs. It occurs after beryllium exposure in genetically susceptible individuals with, most commonly, the HLA-DPβ1 (Glu69) polymorphism [1]. Beryllium particles are slowly washed out, causing delayed onsets of the disease and flare ups long after exposure to beryllium [2, 3]. The clinical, radiological and pathological presentation of CBD is very similar to sarcoidosis. Thus, misdiagnosis is not uncommon, as reported by Fireman et al . [4] and Muller-quernheim et al. [5]. These authors managed to correct the diagnosis of chronic sarcoidosis to CBD in 4–6% of patients, thanks to a careful retrospective screening for beryllium exposure [4, 5]. In CBD, lungs are damaged by diffuse noncaseating granulomas and this may lead to fibrosis. The US Beryllium Case Registry determined the following specific criteria for CBD diagnosis: a beryllium exposure history; relevant clinical and radiological signs (breathlessness, reduced pulmonary capacity and diffuse interstitial opacities); evidence of beryllium sensitisation with positive beryllium lymphocyte proliferation test in blood or in bronchoalveolar lavage (BAL); and histopathological features such as noncaseating granulomas or mononuclear tissue infiltration without any infection. Long-term prognosis of CBD is poor with a mortality rate ranging from 5.8% …

Treatment of recurrent respiratory papillomatosis lung involvement by cidofovir infusion.

Abstract Lung parenchyma involvement in recurrent respiratory papillomatosis (RRP) is rare, can be severe, and has variable outcomes. Although several reports have described the effects of different drugs (interferon alpha, indol-3-carbinol, cidofovir, etc.), there is no standard treatment for lung involvement in respiratory papillomatosis. We discuss herein the controversial effectiveness of cidofovir in light of a new observation of respiratory papillomatosis involving lung parenchyma. The reported case is one of rare pulmonary involvement in RRP and shows the effectiveness of intravenous cidofovir alone on symptoms, high-resolution computed tomography abnormalities, and pulmonary function tests. Aggravation after stopping cidofovir may also be interpreted as an indirect argument for the effectiveness of cidofovir in this case.

Does training respiratory physicians in clinical respiratory physiology and interpretation of pulmonary function tests improve core knowledge

Lung function tests have a major role in respiratory medicine. Training in lung function tests is variable within the European Union. In this study, we have shown that an internship in a lung function tests laboratory significantly improved the technical and diagnostic skills of French respiratory trainees.

Pulmonary Hypertension Complicating Interstitial and Granulomatous Lung Diseases

Pulmonary hypertension (PH) carries a poor prognosis in interstitial lung diseases (ILDs). Its prevalence depends on the underlying condition, the most common being idiopathic pulmonary fibrosis, connective tissue disease-related ILD, sarcoidosis, and pulmonary Langerhans cell histiocytosis (PLCH). Although hypoxic vasoconstriction and loss of pulmonary capillaries are important in the pathogenesis of ILD-associated PH, other mechanisms may play a role, including the release of diverse cytokines and growth factors during fibrogenesis which induce vascular remodeling. This intrinsic vasculopathy may prevail in the venous side in sarcoidosis and PLCH. As a result, a small proportion of ILD patients may exhibit ‘out of proportion’ PH, i.e. more severe than expected from functional impairment (mean pulmonary artery pressure > 35–40 mm Hg). The accuracy of echocardiography for the detection of PH is weak in ILDs. Management of ILD-associated PH mainly relies on supplemental oxygen and lung transplantation in otherwise eligible patients. Treatments targeted to the underlying ILD do not usually affect the course of PH, with the exception of rare cases of nonfibrotic sarcoidosis responding to corticosteroids. Data on the efficacy and safety of pulmonary arterial hypertension-specific agents are lacking. Further controlled trials are warranted and should integrate the concept of disproportionate PH in their design.