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Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the acute respiratory distress syndrome (ARDS). In animal models of ARDS, keratinocyte growth factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown. To test whether KGF can attenuate alveolar injury in a human model of ARDS. Volunteers were randomized to intravenous KGF (60 μg/kg) or placebo for 3 days, before inhaling 50 μg LPS. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury. KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of surfactant protein D, matrix metalloproteinase (MMP)-9, IL-1Ra, granulocyte-macrophage colony-stimulating factor (GM-CSF), and C-reactive protein. In vitro, BAL fluid from KGF-treated subjects inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF-pretreated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor. KGF treatment increases BAL surfactant protein D, a marker of type II alveolar epithelial cell proliferation in a human model of acute lung injury. Additionally, KGF increases alveolar concentrations of the antiinflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF). Clinical trial registered with ISRCTN 98813895.

Laparoscopic procedures require abdominal inflation (pneumoperitoneum), which triggers strong stress responses that typically need high concentrations of sevoflurane to manage. Despite dexmedetomidine's known anesthetic-sparing properties, its specific effects on sevoflurane minimum alveolar concentration for blunting sympathetic response (MAC ) during pneumoperitoneum remain incompletely characterized. This study evaluates dexmedetomidine's impact on sevoflurane requirements for blocking sympathetic responses during laparoscopic pneumoperitoneum. This prospective, randomized, double-blind, placebo-controlled trial enrolled 90 adults (aged 18-45 years) classified as American Society of Anesthesiologists physical status I-II scheduled for elective laparoscopic cholecystectomy. Participants received either saline, low-dose dexmedetomidine (target 0.3 ng/mL), or high-dose dexmedetomidine (target 0.6 ng/mL). We determined sevoflurane MAC using Dixon's up-and-down method, defined as the concentration preventing ≥ 20% increase in heart rate or mean arterial pressure following pneumoperitoneum. Secondary outcomes included hemodynamic responses, emergence time, adverse events, and plasma catecholamine levels. Dexmedetomidine significantly reduced sevoflurane MAC compared to control (4.70% ± 0.18%; 95% confidence interval [CI], 4.61-4.80): to 2.90% ± 0.19% (95% CI, 2.80-3.00) in the low-dose group and to 1.90% ± 0.16% (95% CI, 1.82-1.98) in the high-dose group (both p < 0.001). Patients receiving dexmedetomidine had significantly lower plasma epinephrine and norepinephrine levels following pneumoperitoneum compared to control (p < 0.001), with better hemodynamic stability. Emergence times and adverse event rates remained comparable between groups. Dexmedetomidine produces dose-dependent reductions in sevoflurane requirements for controlling sympathetic responses during pneumoperitoneum while maintaining hemodynamic stability, making it a valuable adjunct for anesthesia in laparoscopic surgery. The Chinese Clinical Trials Registry, ChiCTR2300071257.

High-altitude pulmonary edema occurs in otherwise healthy persons when they are at high elevations. Since β-adrenergic agonists increase clearance of alveolar fluid and attenuate pulmonary edema in animal models, these investigators studied the effect of inhaled salmeterol (a β-adrenergic agonist) or placebo in 37 subjects who were prone to high-altitude pulmonary edema. In addition, nasal transepithelial potential difference, a marker of fluid clearance in distal airways, was studied in 33 mountaineers who were susceptible to this condition and 33 who were resistant to the condition. Prophylactic inhalation of salmeterol halved the incidence of high-altitude edema in susceptible subjects. Nasal transepithelial potential difference was significantly lower in susceptible subjects. Inhalation of salmeterol halved the incidence in susceptible subjects. Pulmonary edema is a life-threatening condition that results from a persistent imbalance between the forces that drive water into the air space in the alveoli and the physiologic mechanisms that remove it. 1 For many years, it was believed that Starling forces and lymphatic drainage accounted entirely for the removal of excess intraalveolar fluid, but it is now clear that an osmotic gradient created by vectorial transepithelial sodium transport plays an important part. Sodium enters the apical membrane of alveolar epithelial cells mainly through amiloride-sensitive cation channels and is transported across the basolateral membrane by ouabain-inhibitable Na + /K + –ATPase. 2 In mice, . . .

Background: Acute lung injury is an important cause of respiratory failure in the critically ill patient. It is caused by damage to the alveolar barrier with subsequent alveolar flooding leading to the development of refractory hypoxaemia. β Agonists stimulate alveolar fluid clearance in animal models of lung injury. In a clinical trial (BALTI-1), intravenous beta agonists reduced extravascular lung water, an effect that took 72 h in contrast with what animal studies suggest. One possible explanation for the delay in change in extravascular lung water is the time required for salbutamol to stimulate alveolar epithelial repair. Objective: To investigate whether salbutamol can stimulate alveolar epithelial repair in vivo and in vitro. Results: Intravenous salbutamol reduced measures of alveolar–capillary permeability in patients with acute respiratory distress syndrome (ARDS). In vitro, salbutamol stimulated both wound repair, and spreading and proliferation of A549 cells and distal lung epithelial cells. Lung lavage fluid from patients treated with salbutamol enhanced wound repair responses compared with placebo treated patients in vitro by an interleukin 1β dependent mechanism. Conclusions: Our in vivo and in vitro work suggests that salbutamol may stimulate epithelial repair—potentially a pharmacological first in ARDS. Clearly establishing the mechanisms and pathways responsible for this is important for the future, and may allow identification of novel therapeutic targets to promote alveolar epithelial repair in humans with ARDS.

This paper reports the efficient generation of human alveolar cells from induced pluripotent stem cells and their expansion in 3D culture. The stable expansion of tissue-specific stem cells in vitro has contributed to research on several organs. Alveolar epithelial type II (AT2) cells function as tissue stem cells in the lung, but robust models for studying human AT2 cells are lacking. Here we report a method for the efficient generation and long-term expansion of alveolar organoids (AOs) harboring SFTPC + alveolar stem cells derived from human induced pluripotent stem cells (hiPSCs). hiPSC-derived SFTPC + cells self-renewed, with transcriptomes and morphology consistent with those of AT2 cells, and were able to differentiate into alveolar epithelial type I (AT1)-like cells. Single-cell RNA-seq of SFTPC + cells and their progenitors demonstrated that their differentiation process and cellular heterogeneity resembled those of developing AT2 cells in vivo . AOs were applicable to drug toxicology studies recapitulating AT2-cell-specific phenotypes. Our methods can help scientists overcome the limitations of current approaches to the modeling of human alveoli and should be useful for disease modeling and regenerative medicine.

Nintedanib, a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis, has anti-fibrotic, anti-inflammatory, and anti-angiogenic activity. We explored the impact of nintedanib on microvascular architecture in a pulmonary fibrosis model. Lung fibrosis was induced in C57Bl/6 mice by intratracheal bleomycin (0.5 mg/kg). Nintedanib was started after the onset of lung pathology (50 mg/kg twice daily, orally). Micro-computed tomography was performed via volumetric assessment. Static lung compliance and forced vital capacity were determined by invasive measurements. Mice were subjected to bronchoalveolar lavage and histologic analyses, or perfused with a casting resin. Microvascular corrosion casts were imaged by scanning electron microscopy and synchrotron radiation tomographic microscopy, and quantified morphometrically. Bleomycin administration resulted in a significant increase in higher-density areas in the lungs detected by micro-computed tomography, which was significantly attenuated by nintedanib. Nintedanib significantly reduced lung fibrosis and vascular proliferation, normalized the distorted microvascular architecture, and was associated with a trend toward improvement in lung function and inflammation. Nintedanib resulted in a prominent improvement in pulmonary microvascular architecture, which outperformed the effect of nintedanib on lung function and inflammation. These findings uncover a potential new mode of action of nintedanib that may contribute to its efficacy in idiopathic pulmonary fibrosis.

Purpose Leukotriene D 4 (LTD 4 ) is a central mediator in asthma inducing bronchoconstriction and profound disturbances in pulmonary gas exchange in asthmatic subjects. The aim of the study was to compare, for the first time, the influence of the bronchodilators salbutamol (400 μg) and ipratropium (80 μg) on lung function changes induced by inhaled LTD 4 . Methods Treatments were evaluated in a randomized, three-period, double-blind, placebo-controlled, cross-over study where spirometric and pulmonary gas exchange indices were followed in 12 subjects with mild asthma before and after LTD 4 challenge. Results Compared with placebo, salbutamol provided significant protection against the fall in FEV 1 (forced expiratory volume in 1 s) after LTD 4 challenge. Salbutamol also abolished the LTD 4 -induced gas exchange disturbances [decreased arterial oxygen tension (PaO 2 ) and increased alveolar–arterial oxygen tension difference (AaPO 2 )]. Ipratropium provided significant but less marked attenuation of the changes in FEV 1 and arterial oxygenation induced by LTD 4 . Conclusion Despite the equal bronchodilatory effects of salbutamol and ipratropium before the challenge with LTD 4 , salbutamol was superior to ipratropium in preventing spirometric and gas exchange abnormalities. This result indicates a broader action of salbutamol on several of the disturbances that contribute to airway obstruction including, for example, exudation of plasma in the airway mucosa. The clinical implication of this new finding is that in this model of acute asthmatic airway obstruction, salbutamol was more effective than ipratropium.

The plasticity of differentiated cells in adult tissues undergoing repair is an area of intense research. Pulmonary alveolar type II cells produce surfactant and function as progenitors in the adult, demonstrating both self-renewal and differentiation into gas exchanging type I cells. In vivo , type I cells are thought to be terminally differentiated and their ability to give rise to alternate lineages has not been reported. Here we show that Hopx becomes restricted to type I cells during development. However, unexpectedly, lineage-labelled Hopx + cells both proliferate and generate type II cells during adult alveolar regrowth following partial pneumonectomy. In clonal 3D culture, single Hopx + type I cells generate organoids composed of type I and type II cells, a process modulated by TGFβ signalling. These findings demonstrate unanticipated plasticity of type I cells and a bidirectional lineage relationship between distinct differentiated alveolar epithelial cell types in vivo and in single-cell culture. Alveoli are the lung’s functional units composed of two major epithelial cell types, type I and type II. Type II cells are adult lung stem cells, but this study shows that differentiated Type I cells can also self-renew and give rise to Type II cells, revealing a bidirectional relationship between lung epithelial cell types.

RationaleVitamin D deficiency has been implicated as a pathogenic factor in sepsis and intensive therapy unit mortality but has not been assessed as a risk factor for acute respiratory distress syndrome (ARDS). Causality of these associations has never been demonstrated.ObjectivesTo determine if ARDS is associated with vitamin D deficiency in a clinical setting and to determine if vitamin D deficiency in experimental models of ARDS influences its severity.MethodsHuman, murine and in vitro primary alveolar epithelial cell work were included in this study.FindingsVitamin D deficiency (plasma 25(OH)D levels <50 nmol/L) was ubiquitous in patients with ARDS and present in the vast majority of patients at risk of developing ARDS following oesophagectomy. In a murine model of intratracheal lipopolysaccharide challenge, dietary-induced vitamin D deficiency resulted in exaggerated alveolar inflammation, epithelial damage and hypoxia. In vitro, vitamin D has trophic effects on primary human alveolar epithelial cells affecting >600 genes. In a clinical setting, pharmacological repletion of vitamin D prior to oesophagectomy reduced the observed changes of in vivo measurements of alveolar capillary damage seen in deficient patients.ConclusionsVitamin D deficiency is common in people who develop ARDS. This deficiency of vitamin D appears to contribute to the development of the condition, and approaches to correct vitamin D deficiency in patients at risk of ARDS should be developed.Trial registrationUKCRN ID 11994.

Epithelial-mesenchymal transition (EMT) is a phenotype conversion that plays a critical role in the development of pulmonary fibrosis (PF). It is known that snail could regulate the progression of EMT. Nuclear factor erythroid 2 related factor 2 (Nrf2), a key regulator of antioxidant defense system, protects cells against oxidative stress. However, it is not known whether Nrf2 regulates snail thereby modulating the development of PF. Here, bleomycin (BLM) was intratracheally injected into both Nrf2-knockout (Nrf2 −/− ) and wild-type mice to compare the development of PF. Rat type II alveolar epithelial cells (RLE-6TN) were treated with a specific Nrf2 activator sulforaphane, or transfected with Nrf2 and snail siRNAs to determine their effects on transforming growth factor β1 (TGF-β1)-induced EMT. We found that BLM-induced EMT and lung fibrosis were more severe in Nrf2 −/− mice compared to wild-type mice. In vitro , sulforaphane treatment attenuated TGF-β1-induced EMT, accompanied by the down-regulation of snail. Inversely, silencing Nrf2 by siRNA enhanced TGF-β1-induced EMT along with increased expression of snail. Interestingly, when snail was silenced by siRNA, sulforaphane treatment was unable to reduce the progression of EMT in RLE-6TN cells. These findings suggest that Nrf2 attenuates EMT and fibrosis process by regulating the expression of snail in PF.