Mesenchymal stromal cells (MSC) have shown potential efficacy in both animal and human trials of acute respiratory distress syndrome (ARDS). Especially during the COVID-19 pandemic, MSC was intensely studied for treating COVID-19-induced ARDS. The purpose of this study is to evaluate the safety and efficacy of MSC in ARDS via a meta-analysis of randomized controlled trials (RCTs). Therefore, a meta-analysis of RCTs of MSC as a therapy for ARDS was conducted. The protocol of this review was registered on Open Science Framework. With no language restriction and according to the “PICOs” principle, searches were conducted on Pubmed and Embase to retrieve any clinical literature on MSC for ARDS. Any RCT, which compared MSC to controls for ARDS, where MSC and controls were intravenously infused, of any dosage, was eligible for inclusion. A total of 13 RCTs, which evaluated MSC versus control for treating ARDS, enrolling a total of 655 cases, met the inclusion criteria and appeared in this meta-analysis. A heterogeneity assessment was carried out using the χ² test, where a P value less than 0.05 was considered significant. The choice of a fixed-effect or a random-effect model was decided by the I² value in each of the analyses. This meta-analysis indicated that there was no significant difference in terms of adverse events between MSC and control for ARDS (OR = 0.64, 95% CI [0.34, 1.20], P = 0.17, and I² = 0%). In comparison with control, MSC could reduce the mortality of ARDS (OR = 0.66, 95% CI [0.46, 0.96], P = 0.03, and I² = 10%). Based on the results of our meta-analysis, the safety of MSC was demonstrated to be non-inferior to that of standard treatment, and MSC may reduce the mortality rate of ARDS. Though the heterogeneity in the main results was low (I² < 25%), more high-quality and large-scale clinical trials are needed to further confirm our findings.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by acute lung inflammation, increased vascular permeability, and hypoxemic respiratory failure. Oxidative stress, driven by excessive reactive oxygen species (ROS), is a key contributor to ARDS pathogenesis, causing cellular damage, inflammation, and alveolar-capillary barrier disruption. This review elucidates the mechanisms of oxidative stress in ARDS, focusing on ROS production via NADPH oxidase (NOX) and mitochondria, which activate pathways like NF-κB and MAPK, promoting pro-inflammatory cytokine release. ROS-induced lipid and protein peroxidation, endothelial dysfunction, and programmed cell death (PCD), including apoptosis, pyroptosis, and ferroptosis, exacerbate lung injury. In COVID-19-related ARDS, SARS-CoV-2 spike protein amplifies mitochondrial ROS, worsening outcomes. Antioxidant therapies falter due to non-specific ROS suppression, patient heterogeneity (e.g., GSTP1 polymorphisms), and poor bioavailability. We propose a model where oxidative stress drives ARDS stages—early alveolar injury and late systemic dysfunction—suggesting targeted therapies like endothelial-specific nanoparticles or ferroptosis inhibitors. Precision medicine using biomarkers (e.g., mtDNA) and gender-specific approaches (e.g., estrogen-Nrf2 regulation) could enhance outcomes. This review bridges mechanistic gaps, critiques therapeutic failures, and advocates novel strategies like mitochondrial-targeted therapies to improve ARDS management.

Background: The investigation of mesenchymal stromal cell (MSC)-conditioned medium or extracellular vesicles (exosomes or microvesicles) as a remedy for acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) has become a fast-growing field in recent years. Our purpose was to conduct a meta-analysis to investigate the efficacy of MSC-derived therapies (MDTs) for ALI/ARDS in animal models. Methods: A meta-analysis of MDTs for ALI/ARDS in animal trials was performed. PubMed and EMBASE were searched to screen relevant preclinical trials with a predetermined search strategy. Results: A total of 17 studies that compared MDT with the ALI control group were included in our study. The pooled result derived from the comparison of the two groups suggested that MDT could significantly reduce the lung injury score (standardized mean difference (SMD) = − 4.02, 95% CI [− 5.28, − 2.23], P < 0.0001) and improve animal survival (OR = − 6.45, 95% CI [2.78, 14.97], P < 0.0001). MDT mitigated the infiltration of neutrophils in alveoli (SMD = − 3.38, 95% CI [− 4.58, − 2.18], P < 0.00001). MDT also reduced the wet-dry weight ratio of the lung (SMD = − 2.34, 95% CI [− 3.42, − 1.26], P < 0.0001) and the total protein in BALF (SMD = − 2.23, 95% CI [− 3.07, − 1.40], P < 0.00001). Furthermore, MDT was found to downregulate proinflammatory mediators such as IL-1, IL-6 and TNF-a and to upregulate anti-inflammatory mediators such as IL-10. Conclusion: MDT reduces lung injury and improves survival in animal ARDS models since it can ameliorate lung permeability, decrease inflammatory cell infiltration, downregulate proinflammatory mediators, and upregulate anti-inflammatory mediators. However, more animal studies and human trials are needed for further investigation.

Over the past decade, global investigations have rigorously assessed the safety and therapeutic potential of mesenchymal stem cells (MSCs) in managing acute respiratory distress syndrome (ARDS). MSCs, obtained from sources like bone marrow, adipose tissue, and umbilical cord, exert therapeutic effects in ARDS primarily through complex paracrine mechanisms, including anti-inflammatory, immunoregulatory, pro-reparative, antioxidant, antimicrobial, and mitochondrial transfer functions. Preclinical studies have consistently demonstrated significant therapeutic benefits. Clinical trials have further confirmed a favorable safety profile, with no significant infusion-related toxicity or serious adverse events observed even at higher doses (up to 10 × 10⁶ cells/kg) or following multiple administrations. Yet, while some early-phase clinical trials have not conclusively demonstrated a significant reduction in mortality among ARDS patients, multiple studies note diminished inflammatory biomarkers, enhanced markers of endothelial and epithelial repair (e.g., angiopoietin-2), and suggestive benefits in subgroups like younger patients or those receiving higher doses of viable cells. MSC-derived therapies, particularly extracellular vesicles and conditioned medium, represent promising “cell-free” strategies that may overcome limitations associated with live-cell therapy. Despite encouraging progress, clinical translation faces challenges, including optimizing cell sources, preparation, dosing, delivery, and developing robust potency assays. Future research should prioritize large, high-quality randomized trials to confirm efficacy across various ARDS etiologies and clinical phenotypes, evaluate repeat dosing, and explore innovative strategies such as gene modification, cellular preconditioning, and combination therapies. Collectively, MSCs and their derivatives hold substantial potential for ARDS treatment, though their widespread application requires further validation and a deeper understanding of their interactions with the complex ARDS microenvironment.

Mesenchymal stromal cell (MSC) therapy is a potential therapy for treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), which was widely studied in the last decade. The purpose of our meta-analysis was to investigate the efficacy of MSCs for simulated infection-induced ALI/ARDS in animal trials. PubMed and EMBASE were searched to screen relevant preclinical trials with a prespecified search strategy. 57 studies met the inclusion criteria and were included in our study. Our meta-analysis showed that MSCs can reduce the lung injury score of ALI caused by lipopolysaccharide or bacteria (standardized mean difference (SMD) = −2.97, 95% CI [−3.64 to −2.30], P < 0.00001) and improve the animals’ survival (odds ratio = 3.64, 95% CI [2.55 to 5.19], P < 0.00001). Our study discovered that MSCs can reduce the wet weight to dry weight ratio of the lung (SMD = −2.58, 95% CI [−3.24 to −1.91], P < 0.00001). The proportion of the alveolar sac in the MSC group was higher than that in the control group (SMD = 1.68, 95% CI [1.22 to 2.13], P < 0.00001). Moreover, our study detected that MSCs can downregulate the levels of proinflammatory factors such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the lung and it can upregulate the level of anti-inflammatory factor IL-10. MSCs were also found to reduce the level of neutrophils and total protein in bronchoalveolar lavage fluid, decrease myeloperoxidase (MPO) activity in the lung, and improve lung compliance. MSC therapy may be a promising treatment for ALI/ARDS since it may mitigate the severity of lung injury, modulate the immune balance, and ameliorate the permeability of lung vessels in ALI/ARDS, thus facilitating lung regeneration and repair.

Double lumen intubation and one-lung ventilation should be applied without delay in cases of traumatic main bronchial rupture. In most cases, when the patients’ vital signs have been stabilized, the repair can be performed. However, when one-lung ventilation is complicated by traumatic wet lung, the mortality rate is likely to be much higher. In this case, the patient experienced a left main bronchial rupture, bilateral traumatic wet lung, and acute respiratory distress syndrome (ARDS) because of severe thoracic trauma. Though the patient was treated with intubation and mechanical ventilation (MV), his oxygenation was still not stable. Thus, veno-venous extracorporeal membrane oxygenation (V-V ECMO) was initiated; upon improvement of oxygenation, the patient received an exploratory thoracotomy. Unfortunately, the rupture proved to be irreparable, resulting in a total left pneumonectomy. As there was severe ARDS caused by trauma, ECMO and ultra-low tidal volume (VT) MV strategy (3 ml/kg) were utilized for lung protection post-op. ECMO was sustained up to the 10th day, and MV until the 20th day, post-operation. With the support of MV, ECMO and other comprehensive measures, the patient made a recovery. V-V ECMO and ultra-low VT MV helped this thoracic trauma patient survive the lung edema period and prevented ventilator associated pneumonia (VAP). In extreme situations, with the support of ECMO, the tidal volume may be lowered to 3 ml/kg.