Distinct effects of intravenous bone marrow-derived mesenchymal stem cell therapy on ischemic and non-ischemic lungs after ischemia-reperfusion injury.

BACKGROUND: The preclinical efficacy of mesenchymal stem cell (MSC) therapy after intravenous infusion has been promising, but clinical studies have yielded only modest results. Although most preclinical studies have focused solely on the ischemic lung, it is crucial to evaluate both lungs after ischemia-reperfusion injury, considering the various mechanisms involved. This study aimed to bridge this gap by assessing the acute effects of bone marrow MSC(BM) infusion before ischemic insult and evaluating both ischemic and non-ischemic lungs after reperfusion. METHODS: Eighteen male Wistar rats (403 ± 23 g) were anesthetized and mechanically ventilated using a protective strategy. After baseline data collection, the animals were randomized to 3 groups (n = 6/group): (1) SHAM; (2) ischemia-reperfusion (IR), and (3) intravenous MSC(BM) infusion followed by IR. Ischemia was induced by complete clamping of the left hilum, followed by 1 h of reperfusion after clamp removal. At the end of the experiment, the right and left lungs (non-ischemic and ischemic, respectively) were collected for immunohistochemistry and molecular biology analysis. RESULTS: MSC(BM)s reduced endothelial cell damage and apoptosis markers and improved markers associated with endothelial cell integrity in both lungs. In addition, gene expression of catalase and nuclear factor erythroid 2-related factor 2 increased after MSC(BM) therapy. In the ischemic lung, MSC(BM) therapy mitigated endothelial cell damage and apoptosis and increased gene expression associated with endothelial cell integrity. Conversely, in the non-ischemic lung, apoptosis gene expression increased in the IR group but not after MSC(BM) therapy. CONCLUSION: This study demonstrates distinct effects of MSC(BM) therapy on ischemic and non-ischemic lungs after ischemia-reperfusion injury. The findings underscore the importance of evaluating both lung types in ischemia-reperfusion studies, offering insights into the therapeutic potential of MSC(BM) therapy in the context of lung injury.

Therapeutic effects of hypoxia-preconditioned bone marrow-derived mesenchymal stromal cells and their extracellular vesicles in experimental pulmonary arterial hypertension.

AIMS: To evaluate BM-MSCs and their extracellular vesicles (EVs) preconditioned with hypoxia or normoxia in experimental pulmonary arterial hypertension (PAH). MAIN METHODS: BM-MSCs were isolated and cultured under normoxia (MSC-N, 21%O2) or hypoxia (MSC-H, 1%O2) for 48 h. EVs were then isolated from MSCs under normoxia (EV-N) or hypoxia (EV-H). PAH was induced in male Wistar rats (n = 35) with monocrotaline (60 mg/kg); control animals (CTRL, n = 7) were treated with saline. On day 14, PAH animals received MSCs or EVs under normoxia or hypoxia, intravenously (n = 7/group). On day 28, right ventricular systolic pressure (RVSP), pulmonary acceleration time (PAT)/pulmonary ejection time (PET), and right ventricular hypertrophy (RVH) index were evaluated. Perivascular collagen content, vascular wall thickness, and endothelium-mesenchymal transition were analyzed. KEY FINDINGS: PAT/PET was lower in the PAH group (0.26 ± 0.02, P < 0.001) than in CTRLs (0.43 ± 0.02) and only increased in the EV-H group (0.33 ± 0.03, P = 0.014). MSC-N (32 ± 6 mmHg, P = 0.036), MSC-H (31 ± 3 mmHg, P = 0.019), EV-N (27 ± 4 mmHg, P < 0.001), and EV-H (26 ± 5 mmHg, P < 0.001) reduced RVSP compared with the PAH group (39 ± 4 mmHg). RVH was higher in the PAH group than in CTRL and reduced after all therapies. All therapies decreased perivascular collagen fiber content, vascular wall thickness, and the expression of endothelial markers remained unaltered; only MSC-H and EV-H decreased expression of mesenchymal markers in pulmonary arterioles. SIGNIFICANCE: MSCs and EVs, under normoxia or hypoxia, reduced right ventricular hypertrophy, perivascular collagen, and vessel wall thickness. Under hypoxia, MSCs and EVs were more effective at improving endothelial to mesenchymal transition in experimental PAH.

Mild hypothermia combined with dexmedetomidine reduced brain, lung, and kidney damage in experimental acute focal ischemic stroke.

BACKGROUND: Sedatives and mild hypothermia alone may yield neuroprotective effects in acute ischemic stroke (AIS). However, the impact of this combination is still under investigation. We compared the effects of the combination of mild hypothermia or normothermia with propofol or dexmedetomidine on brain, lung, and kidney in experimental AIS. AIS-induced Wistar rats (n = 30) were randomly assigned, after 24 h, to normothermia or mild hypothermia (32-35 °C) with propofol or dexmedetomidine. Histologic injury score and molecular biomarkers were evaluated not only in brain, but also in lung and kidney. Hemodynamics, ventilatory parameters, and carotid Doppler ultrasonography were analyzed for 60 min. RESULTS: In brain: (1) hypothermia compared to normothermia, regardless of sedative, decreased tumor necrosis factor (TNF)-α expression and histologic injury score; (2) normothermia + dexmedetomidine reduced TNF-α and histologic injury score compared to normothermia + propofol; (3) hypothermia + dexmedetomidine increased zonula occludens-1 expression compared to normothermia + dexmedetomidine. In lungs: (1) hypothermia + propofol compared to normothermia + propofol reduced TNF-α and histologic injury score; (2) hypothermia + dexmedetomidine compared to normothermia + dexmedetomidine reduced histologic injury score. In kidneys: (1) hypothermia + dexmedetomidine compared to normothermia + dexmedetomidine decreased syndecan expression and histologic injury score; (2) hypothermia + dexmedetomidine compared to hypothermia + propofol decreased histologic injury score. CONCLUSIONS: In experimental AIS, the combination of mild hypothermia with dexmedetomidine reduced brain, lung, and kidney damage.

Effects of different fluid management on lung and kidney during pressure-controlled and pressure-support ventilation in experimental acute lung injury.

Optimal fluid management is critical during mechanical ventilation to mitigate lung damage. Under normovolemia and protective ventilation, pulmonary tensile stress during pressure-support ventilation (PSV) results in comparable lung protection to compressive stress during pressure-controlled ventilation (PCV) in experimental acute lung injury (ALI). It is not yet known whether tensile stress can lead to comparable protection to compressive stress in ALI under a liberal fluid strategy (LF). A conservative fluid strategy (CF) was compared with LF during PSV and PCV on lungs and kidneys in an established model of ALI. Twenty-eight male Wistar rats received endotoxin intratracheally. After 24 h, they were treated with CF (minimum volume of Ringer's lactate to maintain normovolemia and mean arterial pressure ≥70 mmHg) or LF (~4 times higher than CF) combined with PSV or PCV (VT  = 6 ml/kg, PEEP = 3 cmH2 O) for 1 h. Nonventilated animals (n = 4) were used for molecular biology analyses. CF-PSV compared with LF-PSV: (1) decreased the diffuse alveolar damage score (10 [7.8-12] vs. 25 [23-31.5], p = 0.006), mainly due to edema in axial and alveolar parenchyma; (2) increased birefringence for occludin and claudin-4 in lung tissue and expression of zonula-occludens-1 and metalloproteinase-9 in lung. LF compared with CF reduced neutrophil gelatinase-associated lipocalin and interleukin-6 expression in the kidneys in PSV and PCV. In conclusion, CF compared with LF combined with PSV yielded less lung epithelial cell damage in the current model of ALI. However, LF compared with CF resulted in less kidney injury markers, regardless of the ventilatory strategy.

Pros and cons of corticosteroid therapy for COVID-19 patients.

In December 2019, an outbreak of severe pneumonia was reported in Wuhan, China. Later described as COVID-19 (coronavirus disease 2019), this infection caused by a virus from the Coronaviridae family (SARS-CoV-2) has spread globally. Effective therapies for this new disease are urgently needed. In this short communication, we will evaluate the use of corticosteroids as an adjunctive pharmacological therapy in the management of COVID-19 and describe its pros and cons in light of the latest available evidence.

Niclosamide attenuates lung vascular remodeling in experimental pulmonary arterial hypertension.

Despite advances in medical therapy, pulmonary arterial hypertension (PAH) remains an inexorably progressive and highly lethal disease. Signal transducer and activator of transcription (STAT)-3 is one of the main intracellular transcription factors implicated in PAH vascular remodeling. We hypothesized that niclosamide, a STAT3 inhibitor, would reduce vascular remodeling in an established pulmonary arterial hypertension model, thus enhancing cardiac function. Male Wistar rats were treated either with monocrotaline (60 mg/kg), to induce PAH, or saline (C group) by intraperitoneal injection. On day 14, PAH animals were randomly assigned to receive oral (1) saline (PAH-SAL); (2) niclosamide (75 mg/kg/day) (PAH-NICLO); (3) sildenafil (20 mg/kg/day) (PAH-SIL); or (4) niclosamide + sildenafil (PAH-NICLO + SIL), once daily for 14 days. On day 28, right ventricular systolic pressure was lower in all treated groups compared to PAH-SAL. Pulmonary vascular collagen content was lower in PAH-NICLO (37 ± 3%) and PAH-NICLO + SIL (37 ± 6%) compared to PAH-SAL (68 ± 4%), but not in PAH-SIL (52 ± 1%). CD-34, an endothelial cell marker, was higher, while vimentin, a mesenchymal cell marker, was lower in PAH-NICLO and PAH-NICLO + SIL compared to PAH-SAL, suggesting attenuation of endothelial-mesenchymal transition. Expression of STAT3 downstream targets such as transforming growth factor (TGF)-ß, hypoxia-inducible factor (HIF)-1, and provirus integration site for Moloney murine leukemia virus (PIM-1) in lung tissue was reduced in PAH-NICLO and PAH-NICLO + SIL compared to PAH-SAL. In conclusion, niclosamide, with or without sildenafil, mitigated vascular remodeling and improved right ventricle systolic pressure. This new role for a well-established drug may represent a promising therapy for PAH.

Effects of the FGF receptor-1 inhibitor, infigratinib, with or without sildenafil, in experimental pulmonary arterial hypertension.

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is a progressive disease associated with high morbidity and mortality, despite advances in medical therapy. We compared the effects of infigratinib (NVP-BGJ398), a new FGF receptor-1 inhibitor, with or without the PDE-5 inhibitor sildenafil, on vascular function and remodelling as well as on gene expression of signal transducers for receptors of TGF-ß (Smads-1/2/4) and transcription factor of endothelial-mesenchymal transition (Twist-1) in established experimental PAH. Types I and III pro-collagen and TGF-ß expressions in lung fibroblasts were analysed in vitro after the different treatments. EXPERIMENTAL APPROACH: PAH was induced in male Wistar rats with monocrotaline. 14 days later, treatments [sildenafil (SIL), infigratinib (INF) or their combination (SIL+INF)] were given for another 14 days. On Day 28, echocardiography and haemodynamic assays were performed, and lungs and pulmonary vessels were removed for analysis by histology, immunohistochemistry and RT-PCR. Fibroblasts prepared from PAH lungs were also analysed for TGF-ß and pro-collagen. KEY RESULTS: Only the combination of infigratinib and sildenafil significantly improved right ventricular systolic pressure and vascular remodelling parameters (right ventricular hypertrophy, smooth muscle α-actin, vessel wall thickness, and vascular collagen content). Infigratinib may act by reducing gene expression of Smads-1/4 and Twist-1 in lung tissue, as well as TGF-ß and types I and III pro-collagen in lung fibroblasts. CONCLUSIONS AND IMPLICATIONS: In this model of monocrotaline-induced PAH, the combination of the new inhibitor of FGF receptor-1, infigratinib, and sildenafil effectively improved haemodynamics and decreased vascular remodelling.