Mesenchymal stem cells (MSCs) and macrophages are fundamental components of the stem cell niche and function coordinately to regulate haematopoietic stem cell self-renewal and mobilization. Recent studies indicate that mitophagy and healthy mitochondrial function are critical to the survival of stem cells, but how these processes are regulated in MSCs is unknown. Here we show that MSCs manage intracellular oxidative stress by targeting depolarized mitochondria to the plasma membrane via arrestin domain-containing protein 1-mediated microvesicles. The vesicles are then engulfed and re-utilized via a process involving fusion by macrophages, resulting in enhanced bioenergetics. Furthermore, we show that MSCs simultaneously shed micro RNA-containing exosomes that inhibit macrophage activation by suppressing Toll-like receptor signalling, thereby de-sensitizing macrophages to the ingested mitochondria. Collectively, these studies mechanistically link mitophagy and MSC survival with macrophage function, thereby providing a physiologically relevant context for the innate immunomodulatory activity of MSCs.

Patients with chronic obstructive pulmonary disease (COPD) often lose weight during the course of their disease. We hypothesized that this may be due to skeletal muscle apoptosis. To investigate this possibility, we obtained quadriceps femoris biopsies in 15 patients with COPD (8 with normal body mass index [BMI] and 7 with low [< 20 kg/m2] BMI), 8 healthy volunteers, and 6 sedentary subjects undergoing orthopedic surgery (both groups with normal BMI). Skeletal muscle apoptosis was assessed by the transferase–mediated dUTP nick end labeling (TUNEL) technique and the immunodetection of poly-(ADP-ribose)-polymerase proteolytic fragments. Exercise tolerance on a cycloergometer was also determined in patients with COPD. We found that skeletal muscle apoptosis (by both techniques) was increased in patients with COPD and low BMI as compared with the other three groups (p < 0.005). In patients with COPD, BMI was inversely related to skeletal muscle apoptosis (TUNEL, p = 0.009), and it was better correlated with exercise capacity (p = 0.006) than with the degree of airflow obstruction present (p = 0.02). Markers of skeletal muscle apoptosis were not related to any of the measured lung function variables. This study shows that skeletal muscle apoptosis (1) is increased in patients with COPD having low BMI; and (2) is associated with a lower exercise tolerance despite a similar degree of lung function impairment.

Physiologic adaptations after an 8-wk endurance training program were examined in 13 patients with chronic obstructive pulmonary disease (COPD) (age, 64 ± 4 [SD] yr; FEV₁, 43 ± 9% pred; PaO₂ , 72 ± 8 mm Hg; and PaCO₂ , 36 ± 2 mm Hg) and in eight healthy sedentary control subjects (61 ± 4 yr). Both pre- and post-training studies included: (1) whole-body oxygen consumption (V˙ o ₂) and one-leg O ₂ uptake (V˙ o _2leg) during exercise; and (2) intracellular pH (pHi) and inorganic phosphate to phosphocreatine ratio ([Pi]/[PCr]) during exercise; and half-time of [PCr] recovery. After training, the two groups increased peak V˙ o ₂ (p < 0.05 each) and showed a similar fall in submaximal femoral venous lactate levels (p < 0.05 each). However, control subjects increased peak V˙ e (p < 0.01) and raised peak O ₂ delivery (p = 0.05), not shown in patients with COPD. Both groups increased post-training O ₂ extraction ratio (p < 0.05). The most consistent finding, however, was in patients with COPD, who had a substantial improvement in cellular bioenergetics: (1) half-time of [PCr] recovery fell from 50 ± 8 to 34 ± 7 s (p = 0.02); and (2) at a given submaximal work rate, [Pi]/[PCr] ratio decreased and pHi increased (p < 0.05 each). We conclude that beneficial effects of training in patients with COPD essentially occurred at muscle level during submaximal exercise.

Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. It is characterized by a chronic, progressive, fibrotic interstitial lung disease of unknown cause that occurs primarily in older adults. Its prevalence and incidence have appeared to be increasing over the last decades. Despite its unknown nature, several genetic and environmental factors have been associated with IPF. Moreover, its natural history is variable, but could change depending on the currently suggested phenotypes: rapidly progressive IPF, familial, combined pulmonary fibrosis and emphysema, pulmonary hypertension, and that associated with connective tissue diseases. Early recognition and accurate staging are likely to improve outcomes and induce a prompt initiation of antifibrotics therapy. Treatment is expected to be more effective in the early stages of the disease, while developments in treatment aim to improve the current median survival of 3–4 years after diagnosis.

Pirfenidone, a pleiotropic anti-fibrotic treatment, has been shown to slow down disease progression of idiopathic pulmonary fibrosis (IPF), a fatal and devastating lung disease. Rapamycin, an inhibitor of fibroblast proliferation could be a potential anti-fibrotic drug to improve the effects of pirfenidone. Primary lung fibroblasts from IPF patients and human alveolar epithelial cells (A549) were treated in vitro with pirfenidone and rapamycin in the presence or absence of transforming growth factor β1 (TGF−β). Extracellular matrix protein and gene expression of markers involved in lung fibrosis (tenascin-c, fibronectin, collagen I [COL1A1], collagen III [COL3A1] and α-smooth muscle actin [α-SMA]) were analyzed. A cell migration assay in pirfenidone, rapamycin and TGF−β-containing media was performed. Gene and protein expression of tenascin-c and fibronectin of fibrotic fibroblasts were reduced by pirfenidone or rapamycin treatment. Pirfenidone-rapamycin treatment did not revert the epithelial to mesenchymal transition pathway activated by TGF−β. However, the drug combination significantly abrogated fibroblast to myofibroblast transition. The inhibitory effect of pirfenidone on fibroblast migration in the scratch-wound assay was potentiated by rapamycin combination. These findings indicate that the combination of pirfenidone and rapamycin widen the inhibition range of fibrogenic markers and prevents fibroblast migration. These results would open a new line of research for an anti-fibrotic combination therapeutic approach.