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BackgroundSilicosis is an occupational disease that affects workers who inhale silica particles, leading to extensive lung fibrosis and ultimately causing respiratory failure. Mesenchymal stromal cells (MSCs) have been shown to exert therapeutic effects in lung diseases and represent an alternative treatment for silicosis. Recently, it has been suggested that similar effects can be achieved by the therapeutic use of extracellular vesicles (EVs) obtained from MSCs. The aim of this study was to investigate the effects of adipose-tissue-derived MSCs (AD-MSCs) or their EVs in a model of silicosis.MethodsSilicosis was induced by intratracheal instillation of silica in C57BL/6 mice. After the onset of disease, animals received saline, AD-MSCs, or EVs, intratracheally.ResultsAt day 30, AD-MSCs and EVs led to a reduction in collagen fiber content, size of granuloma, and in the number of macrophages inside granuloma and in the alveolar septa. In addition, the expression levels of interleukin 1β and transforming growth factor beta in the lungs were decreased. Higher dose of EVs also reduced lung static elastance when compared with the untreated silicosis group.ConclusionsBoth AD-MSCs and EVs, locally delivered, ameliorated fibrosis and inflammation, but dose-enhanced EVs yielded better therapeutic outcomes in this model of silicosis.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0802-3) contains supplementary material, which is available to authorized users.

We hypothesized that infusion of bone marrow mononuclear cells (BMMCs) in the late stages of silica-induced damage would reduce the remodelling process in a murine model of silicosis. C57BL/6 mice were assigned to 2 groups. In the SIL group, mice were instilled with a silica particle suspension intratracheally. Control (C) mice received saline under the same protocol. On the 40th day, some of the animals from both groups were killed. The others were treated with either saline or BMMCs (1×106cells) intravenously (C+BMMC and SIL+BMMC), and the mice were killed 70 days after the start of the protocol. In the mice in the SIL+BMMC group, collagen deposition, the presence of silica particles inside nodules, the presence of macrophages and cells reactive for inducible nitric oxide synthase were reduced. Lung parameters also improved. Beyond that, the total and differential cellularity of bronchoalveolar lavage fluid, immunoexpression of transforming growth factor-β, the number of T regulatory cells and apoptosis were increased. However, the presence of male donor cells in lung tissue was not observed using GFP+ cells (40d) or Y chromosome DNA (70d). Therefore, BMMC therapy in the late stages of experimental silicosis improved lung function by diminishing fibrosis but inflammatory cells persisted, which could be related to expansion of T regulatory cells, responsible for the beneficial effects of cell therapy.

Aims-To determine if the failure of neonatal pulmonary arteries to dilate is due to a lack of nitric oxide synthase (NOS). Methods-A monoclonal antibody to endothelial NOS was used to demonstrate the distribution and density of NOS in the developing porcine lung after a period in hypobaric hypoxia. Newborn piglets were made hypertensive by exposure to hypobaric hypoxia (50.8 kPa) from < 5 minutes of age to 2.5 days of age, 3-6 days of age or 14-17 days of age. A semiquantitative scoring system was used to assess the distribution of endothelial NOS by light microscopy. Results-NOS was present in the arteries in all hypoxic animals. However, hypoxia from birth caused a reduction in NOS compared with those lungs normal at birth and those normal at 3 days. Hypoxia from 3-6 days led to a high density of NOS compared with normal lungs at 6 days. Hypoxia from 14-17 days had little eVect on the amount of NOS. On recovery in room air after exposure to hypoxia from birth there was a transient increase in endothelial NOS after three days of recovery, mirroring that seen at three days in normal animals. Conclusions-Suppression of NOS production in the first few days of life may contribute to pulmonary hypertension in neonates. (Arch Dis Child 1997;77:F16-F22) Keywords: pulmonary circulation; nitric oxide synthase; hypoxia; endothelium; piglets Pulmonary hypertension is a major cause of mortality and morbidity in the newborn period and is characterised by failure of the pulmonary arteries to dilate. This is normally accompanied by changes in endothelial and smooth muscle cell shape and cytoskeletal composition.1 The mechanisms causing these changes are not completely understood, but endogenous nitric oxide produced from L-arginine by nitric oxide synthase (NOS) probably has an important role. The type III (endothelial) form of NOS is present in normal porcine pulmonary vessels at birth and increases to a maximum at 2-3 days of age before reducing to the lower adult level.2 A postnatal decrease has also been described in sheep and rats.3 4Hypoxia is a common cause of failure of the pulmonary arteries to dilate. The pulmonary arteries of newborn piglets made hypertensive by exposure to hypobaric hypoxia for three days showed a loss of endothelium dependent, acetylcholine induced vasodilatation, but continued to dilate in response to nitric oxide, although this response was attenuated.5 Inhaled NO reduces pulmonary artery pressure in hypertensive 1 to 2 day old piglets, 6 and is eVective in the treatment of hypoxic newborn babies.7 8 Failure to dilate in hypoxic newborn humans and animals might be attributable to a reduction in the amount of endothelial NOS.This study aimed to determine whether there were changes in the amount of endothelial NOS in the presence of pulmonary hypertension after hypobaric hypoxic exposure in the newborn period, and also to determine whether any changes were reversible on return to normoxia. MethodsLarge White piglets delivered naturally at term were used. Animals were randomly allocated...