evaluation-right-ventricular-function-experimental-models-pulmonary

Evaluation of Right Ventricular Function in Experimental Models of Pulmonary Arterial Hypertension

Pulmonary hypertension (PH) is a chronic condition associated with reduced survival, making it a critical area of research. Experimental models of PH have ...

Federal University of Rio de Janeir

Federal University of Rio de Janeiro

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.

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

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)-β, 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.

Niclosamide attenuates lung vascular remodeling in experimental pulmonary arterial hypertension.

Acute ischemic stroke is associated with pulmonary complications, and often dexmedetomidine and propofol are used to decrease cerebral metabolic rate. However, it is unknown the immunomodulatory actions of dexmedetomidine and propofol on brain and lungs during acute ischemic stroke. The effects of dexmedetomidine and propofol were compared on perilesional brain tissue and lung damage after acute ischemic stroke in rats. Further, the mean amount of both sedatives was directly evaluated on alveolar macrophages and lung endothelial cells primarily extracted 24-h after acute ischemic stroke. In twenty-five Wistar rats, ischemic stroke was induced and after 24-h treated with sodium thiopental (STROKE), dexmedetomidine and propofol. Dexmedetomidine, compared to STROKE, reduced diffuse alveolar damage score [median(interquartile range); 12(7.8-15.3) vs. 19.5(18-24), p = 0.007)], bronchoconstriction index [2.28(2.08-2.36) vs. 2.64(2.53-2.77), p = 0.006], and TNF-α expression (p = 0.0003), while propofol increased VCAM-1 expression compared to STROKE (p = 0.0004). In perilesional brain tissue, dexmedetomidine, compared to STROKE, decreased TNF-α (p = 0.010), while propofol increased VCAM-1 compared to STROKE (p = 0.024). In alveolar macrophages and endothelial cells, dexmedetomidine decreased IL-6 and IL-1β compared to STROKE (p = 0.002, and p = 0.040, respectively), and reduced IL-1β compared to propofol (p = 0.014). Dexmedetomidine, but not propofol, induced brain and lung protection in experimental acute ischemic stroke.

Comparative effects of dexmedetomidine and propofol on brain and lung damage in experimental acute ischemic stroke.

Although bone marrow-derived mesenchymal stromal cells (MSCs) have demonstrated success in pre-clinical studies, they have shown only mild therapeutic effects in clinical trials. Hypoxia pre-conditioning may optimize the performance of bone marrow-derived MSCs because it better reflects the physiological conditions of their origin. It is not known whether changes in the protein profile caused by hypoxia in MSCs can be extended to the extracellular vesicles (EVs) released from them. The aim of this study was to evaluate the proteomics profile of MSCs and their EVs under normoxic and hypoxic conditions.

Proteomics profile of mesenchymal stromal cells and extracellular vesicles in normoxic and hypoxic conditions.

In experimental sepsis, functional and morphological effects of bone marrow-derived mononuclear cell (BMDMC) administration in lung tissue have been evaluated 1 and 7 days after therapy. However, to date no study has evaluated the early effects of BMDMCs in both lung and kidney in experimental polymicrobial sepsis.

Early effects of bone marrow-derived mononuclear cells on lung and kidney in experimental sepsis.

Patients on mechanical ventilation may receive intravenous fluids via restrictive or liberal fluid management. A clear and objective differentiation between restrictive and liberal fluid management strategies is lacking in the literature. The liberal approach has been described as involving fluid rates ranging from 1.2 to 12 times higher than the restrictive approach. A restrictive fluid management may lead to hypoperfusion and distal organ damage, and a liberal fluid strategy may result in endothelial shear stress and glycocalyx damage, cardiovascular complications, lung edema, and distal organ dysfunction. The association between fluid and mechanical ventilation strategies and how they interact toward ventilator-induced lung injury (VILI) could potentiate the damage. For instance, the combination of a liberal fluids and pressure-support ventilation, but not pressure control ventilation, may lead to further lung damage in experimental models of acute lung injury. Moreover, under liberal fluid management, the application of high positive end-expiratory pressure (PEEP) or an abrupt decrease in PEEP yielded higher endothelial cell damage in the lungs. Nevertheless, the translational aspects of these findings are scarce. The aim of this narrative review is to provide better understanding of the interaction between different fluid and ventilation strategies and how these interactions may affect lung and distal organs. The weaning phase of mechanical ventilation and the deresuscitation phase are not explored in this review.

Fluid management strategies and their interaction with mechanical ventilation: from experimental studies to clinical practice.

To evaluate BM-MSCs and their extracellular vesicles (EVs) preconditioned with hypoxia or normoxia in experimental pulmonary arterial hypertension (PAH).

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

We aimed to evaluate the pulmonary and cerebral effects of low-tidal volume ventilation in pressure-support (PSV) and pressure-controlled (PCV) modes at two PEEP levels in acute ischemic stroke (AIS).

Pressure-support compared with pressure-controlled ventilation mitigates lung and brain injury in experimental acute ischemic stroke in rats.

Non-invasive respiratory support (conventional oxygen therapy [COT], non-invasive ventilation [NIV], high-flow nasal oxygen [HFNO], and NIV alternated with HFNO [NIV + HFNO] may reduce the need for invasive mechanical ventilation (IMV) in patients with COVID-19. The outcome of patients treated non-invasively depends on clinical severity at admission. We assessed the need for IMV according to NIV, HFNO, and NIV + HFNO in patients with COVID-19 according to disease severity and evaluated in-hospital survival rates and hospital and intensive care unit (ICU) lengths of stay.

Comparison between high-flow nasal oxygen (HFNO) alternated with non-invasive ventilation (NIV) and HFNO and NIV alone in patients with COVID-19: a retrospective cohort study.

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.

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

This study aimed to develop prognostic models for predicting the need for invasive mechanical ventilation (IMV) in intensive care unit (ICU) patients with COVID-19 and compare their performance with the Respiratory rate-OXygenation (ROX) index.

Article	Year
Pros and cons of corticosteroid therapy for COVID-19 patients. Respiratory physiology & neurobiology\| PubMed ID: 32659271	2020
Niclosamide attenuates lung vascular remodeling in experimental pulmonary arterial hypertension. European journal of pharmacology\| PubMed ID: 32795515	2020
Comparative effects of dexmedetomidine and propofol on brain and lung damage in experimental acute ischemic stroke. Scientific reports\| PubMed ID: 34848804	2021
Proteomics profile of mesenchymal stromal cells and extracellular vesicles in normoxic and hypoxic conditions. Cytotherapy\| PubMed ID: 36192337	2022
Early effects of bone marrow-derived mononuclear cells on lung and kidney in experimental sepsis. Respiratory physiology & neurobiology\| PubMed ID: 36460253	2023
Fluid management strategies and their interaction with mechanical ventilation: from experimental studies to clinical practice. Intensive care medicine experimental\| PubMed ID: 37474816	2023
Therapeutic effects of hypoxia-preconditioned bone marrow-derived mesenchymal stromal cells and their extracellular vesicles in experimental pulmonary arterial hypertension. Life sciences\| PubMed ID: 37517581	2023
Pressure-support compared with pressure-controlled ventilation mitigates lung and brain injury in experimental acute ischemic stroke in rats. Intensive care medicine experimental\| PubMed ID: 38102452	2023
Comparison between high-flow nasal oxygen (HFNO) alternated with non-invasive ventilation (NIV) and HFNO and NIV alone in patients with COVID-19: a retrospective cohort study. European journal of medical research\| PubMed ID: 38649940	2024
Distinct effects of intravenous bone marrow-derived mesenchymal stem cell therapy on ischemic and non-ischemic lungs after ischemia-reperfusion injury. Cytotherapy\| PubMed ID: 39115513	2024
Derivation and external validation of predictive models for invasive mechanical ventilation in intensive care unit patients with COVID-19. Annals of intensive care\| PubMed ID: 39167241	2024

Pedro Leme Silva

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