Background. Several studies demonstrated that mesenchymal stem cells (MSCs) reverse acute kidney injury (AKI) by a paracrine mechanism rather than by MSC transdifferentiation. We recently demonstrated that microvesicles (MVs) released from MSCs may account for this paracrine mechanism by a horizontal transfer of messenger RNA and microRNA. Methods. MVs isolated from MSCs were injected intravenously in rats (30 μg/rat) immediately after monolateral nephrectomy and renal artery and vein occlusion for 45 min. To evaluate the MV effects on AKI induced by ischaemia–reperfusion injury (IRI), the animals were divided into different groups: normal rats (n = 4), sham-operated rats (n = 6), IRI rats (n = 6), IRI + MV rats (n = 6), and IRI + RNase-MV rats (n = 6), and all animals were sacrificed at Day 2 after the operation. To evaluate the chronic kidney damage consequent to IRI, the rats were divided into different groups: sham-operated rats (n = 6) and IRI rats (n = 6), IRI + MV rats (n = 6), and all animal were sacrificed 6 months after the operation. Results. We found that a single administration of MVs, immediately after IRI, protects rats from AKI by inhibiting apoptosis and stimulating tubular epithelial cell proliferation. The MVs also significantly reduced the impairment of renal function. Pretreatment of MVs with RNase to inactivate their RNA cargo abrogated these protective effects. Moreover, MVs by reducing the acute injury also protected from later chronic kidney disease. Conclusion. MVs released from MSCs protect from AKI induced by ischaemia reperfusion injury and from subsequent chronic renal damage. This suggest that MVs could be exploited as a potential new therapeutic approach.

Twenty-four anesthetized piglets ventilated with a range of tidal volume and respiratory rate developed widespread lung injury above a threshold of 12 J/min. This finding suggests that mechanical power applied may be taken into account for ventilator-induced lung injury prevention. Supplemental Digital Content is available in the text. Background: The ventilator works mechanically on the lung parenchyma. The authors set out to obtain the proof of concept that ventilator-induced lung injury (VILI) depends on the mechanical power applied to the lung. Methods: Mechanical power was defined as the function of transpulmonary pressure, tidal volume (TV), and respiratory rate. Three piglets were ventilated with a mechanical power known to be lethal (TV, 38 ml/kg; plateau pressure, 27 cm H₂O; and respiratory rate, 15 breaths/min). Other groups (three piglets each) were ventilated with the same TV per kilogram and transpulmonary pressure but at the respiratory rates of 12, 9, 6, and 3 breaths/min. The authors identified a mechanical power threshold for VILI and did nine additional experiments at the respiratory rate of 35 breaths/min and mechanical power below (TV 11 ml/kg) and above (TV 22 ml/kg) the threshold. Results: In the 15 experiments to detect the threshold for VILI, up to a mechanical power of approximately 12 J/min (respiratory rate, 9 breaths/min), the computed tomography scans showed mostly isolated densities, whereas at the mechanical power above approximately 12 J/min, all piglets developed whole-lung edema. In the nine confirmatory experiments, the five piglets ventilated above the power threshold developed VILI, but the four piglets ventilated below did not. By grouping all 24 piglets, the authors found a significant relationship between the mechanical power applied to the lung and the increase in lung weight (r ² = 0.41, P = 0.001) and lung elastance (r ² = 0.33, P < 0.01) and decrease in Pao ₂/Fio ₂ (r ² = 0.40, P < 0.001) at the end of the study. Conclusion: In piglets, VILI develops if a mechanical power threshold is exceeded.

Adrenocorticotropic hormone and α-, β-, and γ-melanocyte-stimulating hormones, collectively called melanocortin peptides, exert multiple effects upon the host. These effects range from modulation of fever and inflammation to control of food intake, autonomic functions, and exocrine secretions. Recognition and cloning of five melanocortin receptors (MCRs) has greatly improved understanding of peptide-target cell interactions. Preclinical investigations indicate that activation of certain MCR subtypes, primarily MC1R and MC3R, could be a novel strategy to control inflammatory disorders. As a consequence of reduced translocation of the nuclear factor κB to the nucleus, MCR activation causes a collective reduction of the major molecules involved in the inflammatory process. Therefore, anti-inflammatory influences are broad and are not restricted to a specific mediator. Short half-life and lack of selectivity could be an obstacle to the use of the natural melanocortins. However, design and synthesis of new MCR ligands with selective chemical properties are already in progress. This review examines how marshaling MCR could control inflammation.

Several studies suggested the presence of stem cells in the adult normal human liver; however, a population with stem cell properties has not yet been isolated. The purpose of the present study was to identify and characterize progenitor cells in normal adult human liver. By stringent conditions of liver cell cultures, we isolated and characterized a population of human liver stem cells (HLSCs). HLSCs expressed the mesenchymal stem cell markers CD29, CD73, CD44, and CD90 but not the hematopoietic stem cell markers CD34, CD45, CD117, and CD133. HLSCs were also positive for vimentin and nestin, a stem cell marker. The absence of staining for cytokeratin-19, CD117, and CD34 indicated that HLSCs were not oval stem cells. In addition, HLSCs expressed albumin, alpha-fetoprotein, and in a small percentage of cells, cytokeratin-8 and cytokeratin-18, indicating a partial commitment to hepatic cells. HLSCs differentiated in mature hepatocytes when cultured in the presence of hepatocyte growth factor and fibroblast growth factor 4, as indicated by the expression of functional cytochrome P450, albumin, and urea production. Under this condition, HLSCs downregulated alpha-fetoprotein and expressed cytokeratin-8 and cytokeratin-18. HLSCs were also able to undergo osteogenic and endothelial differentiation when cultured in the appropriated differentiation media, but they did not undergo lipogenic differentiation. Moreover, HLSCs differentiated in insulin-producing islet-like structures. In vivo, HLSCs contributed to regeneration of the liver parenchyma in severe-combined immunodeficient mice. In conclusion, we here identified a pluripotent progenitor population in adult human liver that could provide a basis for cell therapy strategies.

Rationale: Unphysiologic strain (the ratio between tidal volume and functional residual capacity) and stress (the transpulmonary pressure) can cause ventilator-induced lung damage. Objectives: To identify a strain–stress threshold (if any) above which ventilator-induced lung damage can occur. Methods: Twenty-nine healthy pigs were mechanically ventilated for 54 hours with a tidal volume producing a strain between 0.45 and 3.30. Ventilator-induced lung damage was defined as net increase in lung weight. Measurements and Main Results: Initial lung weight and functional residual capacity were measured with computed tomography. Final lung weight was measured using a balance. After setting tidal volume, data collection included respiratory system mechanics, gas exchange and hemodynamics (every 6 h); cytokine levels in serum (every 12 h) and bronchoalveolar lavage fluid (end of the experiment); and blood laboratory examination (start and end of the experiment). Two clusters of animals could be clearly identified: animals that increased their lung weight (n = 14) and those that did not (n = 15). Tidal volume was 38 ± 9 ml/kg in the former and 22 ± 8 ml/kg in the latter group, corresponding to a strain of 2.16 ± 0.58 and 1.29 ± 0.57 and a stress of 13 ± 5 and 8 ± 3 cm H₂O, respectively. Lung weight gain was associated with deterioration in respiratory system mechanics, gas exchange, and hemodynamics, pulmonary and systemic inflammation and multiple organ dysfunction. Conclusions: In healthy pigs, ventilator-induced lung damage develops only when a strain greater than 1.5–2 is reached or overcome. Because of differences in intrinsic lung properties, caution is warranted in translating these findings to humans.