American journal of physiology. Lung cellular and molecular physiology最新文献

Excessive mucus in the airways is an underlying pathological feature of many airway diseases, including asthma. Therapeutic options to reduce mucus production in the airways remain limited. One possible therapeutic target is the airway sympathetic nerves. Although lung sympathetic innervation has been considered sparse, sympathetic nerves secrete neurotransmitters that act on adrenergic receptors, including β₂-adrenergic receptor (β₂AR). Interestingly, in experimental models, chronic use of β₂AR agonists can augment mucus secretion. Thus, in the present study, we tested the hypothesis that airway sympathetic nerves regulate mucus production in the airway in response to the type 2 cytokine interleukin 13 (IL-13). We performed airway sympathectomy using intranasal instillation of the synthetic neurotoxin 6-hydroxydopamine (6-OHDA). Airway sympathectomy attenuated multiple IL-13-mediated airway deficits, including density of goblet cells containing neutral mucins, transcriptional ratio of mucin 5ac (Muc5ac) to mucin 5b (Muc5b), and airway elastance and tissue damping. Although total Muc5ac and Muc5b transcript levels and Muc5ac and Muc5b protein levels in bronchoalveolar lavage were not significantly altered, these changes suggest that airway sympathectomy modifies goblet cell phenotype and mucin composition. Airway sympathectomy also dampened IL-13-mediated increases in total lung transcripts important for regulating allergic responses, including interleukin 6, complement component 3, and colony-stimulating factor. This study reveals that airway sympathetic nerves regulate physiologic, molecular, and inflammatory responses to type 2 (IL-13-mediated) airway inflammation and raises the possibility that they may serve as potential targets for therapeutic intervention.NEW & NOTEWORTHY The role of airway sympathetic nerves in regulating airway responses remains largely undefined. We demonstrated that chemical depletion of airway sympathetic nerves attenuates specific IL-13-induced airway deficits at the molecular, cellular, and functional level. Our data suggest that airway sympathetic nerves may represent novel therapeutic targets to alleviate some pathologic features due to type 2 (IL-13-mediated) airway inflammation.

Biomarkers based on volatile organic compounds (VOCs) measured in human breath have been investigated in a wide range of diseases. However, the excitement surrounding such biomarkers has not yet translated to the discovery of any that are ready for clinical implementation. A lack of standardization in sampling and analysis has been identified as a key obstacle to the validation of potential biomarkers in multicenter studies. Some progress toward standardization has been made, but further progress is required to optimize sampling protocols and account for the confounding factors identified. This review highlights the important role that in silico (i.e., computational modeling) methods can play in addressing these gaps. Moreover, we discuss their potential for targeting and validating disease biomarkers by mechanistically linking them to the underlying metabolomic processes. We explore pertinent examples of mathematical, computational, and machine learning models that have proven useful in similar contexts, such as the development of fractional exhaled nitric oxide sampling standards. We then propose a roadmap outlining how existing and new modeling approaches can be applied to the problem of standardization in breathomics research.

Session V of the inaugural biennial Research Symposium on Pulmonary Injury and Repair of the Endothelium showcased cutting-edge research on pulmonary endothelial crosstalk with end organs and its role in vascular disease. Growing evidence suggests that communication between injured organs and distal vascular beds plays a critical role in the pathogenesis of complex conditions such as sepsis, acute respiratory distress syndrome, pulmonary arterial hypertension, and heart failure with preserved ejection fraction. Circulating mediators-including heparan sulfate fragments, proinflammatory cytokines, mitochondrial damage-associated molecular patterns, bone morphogenetic protein 9, bile acids, and nitric oxide-have emerged as key factors linking pulmonary endothelial dysfunction to neural impairment, acute kidney injury, subclinical liver injury, and left-sided heart disease. This review highlights recent advances in the field, identifies critical knowledge gaps, and outlines future research directions aimed at elucidating mechanisms of multiorgan dysfunction and identifying novel therapeutic targets.

Cystic fibrosis (CF) is characterized by impaired mucociliary clearance and pulmonary infections. Accumulating evidence suggests that fundamentally abnormal inflammatory responses also contribute to CF pathology. Transforming growth factor β (TGF-β), a pleiotropic cytokine, is a modifier of CF lung disease; its mechanism of action in CF is unclear. Previous studies have shown that TGF-β induces interleukin-6 (IL-6) secretion from lung epithelium, which may drive worse pulmonary outcomes in CF and other lung diseases. However, the nature of the TGF-β/IL-6 relationship in CF is not fully understood. In this study, we demonstrated that TGF-β and IL-6 concentrations were positively associated in bronchoalveolar lavage fluid from children with CF. Furthermore, pulmonary TGF-β exposure in a CF mouse model induced heightened IL-6 secretion when compared with non-CF mice. CF airway epithelial cells had increased IL-6 secretion and phosphoinositide 3-kinase (PI3K) signaling after TGF-β exposure. In wild-type airway epithelium, TGF-β exposure and cystic fibrosis transmembrane conductance regulator (CFTR) inhibition synergistically provoked IL-6 secretion. Restoration of CFTR function by a CFTR modulator and inhibition of PI3K signaling both normalized IL-6 secretion from CF airway epithelial cells. These data indicate that TGF-β drives abnormal IL-6 secretion via the PI3K pathway in the CF airway, demonstrating an inherent inflammatory abnormality in CF and suggesting potential therapeutic targets.NEW & NOTEWORTHY The etiology of IL-6 oversecretion in cystic fibrosis (CF) is unclear, as is the mechanism of CF lung disease modification by TGF-β. We show that TGF-β induces IL-6 oversecretion in human and mouse models of CF. In mechanistic studies, we further demonstrate that loss of CFTR function drives increased IL-6 secretion via the PI3K pathway downstream of TGF-β. Treatment of CF airway epithelial cells with a CFTR modulator rescues this IL-6 oversecretion.

Obesity is a risk factor for acute respiratory distress syndrome (ARDS). We previously showed that obesity is linked to increased lung injury and bronchoalveolar lavage fluid (BALF) fatty acids in a hyperoxic model of ARDS. We sought to expand our understanding of this association and examined the effect of obesity on β-oxidation (FAO), the mitochondrial process of breaking down fatty acids, in alveolar epithelial type 2 cells (AEC2s) in hyperoxia-induced ARDS. AEC2 were isolated from mice receiving 60% versus 10% fat diet. Carnitine palmitoyltransferase 1A (CPT1A) mediates the transport of fatty acids into mitochondria for subsequent FAO. Cpt1a^loxp/loxpSftpc^CreERT2+/- mice were generated with AEC2-specific CPT1A downregulation. Obesity was associated with intracellular lipid accumulation and increased expression of CPT1A in AEC2 after hyperoxia. Mitochondrial FAO; however, was significantly transcriptionally downregulated in AEC2 of obese mice compared with lean mice after hyperoxia. AEC2 from obese mice exhibited more severe mitochondrial bioenergetic failure and reduced ATP production after hyperoxia compared with lean mice. Consistent with earlier reports linking FAO perturbation to surfactant impairment, we also observed that high-fat diet was associated with reduced surfactant-related phospholipids in hyperoxic AEC2 and increased BALF surface tension, although obese Cpt1a^loxp/loxpSftpc^CreERT2+/- mice were not protected from increased lung injury. In a reanalysis of a human single-cell lung atlas of COVID-19 ARDS, the downregulation of the FAO signature in AEC2 was significant only in obese, and not lean, patients with ARDS compared with controls. These findings demonstrate a previously underappreciated effect of diet on AEC2 function in acute lung injury.NEW & NOTEWORTHY High-fat diet obesity is linked to increased lung injury and bronchoalveolar lavage fluid (BALF) fatty acids in a hyperoxic ARDS model. In the present study, obesity not only upregulated intracellular lipids and effectors of fatty acid mitochondrial import but also was associated with downregulated fatty acid oxidation and reduced ATP production in alveolar epithelial type 2 cells after injury. Hyperoxic AEC2 from obese mice had reduced phospholipids, and obese mice had increased BALF surface tension after injury.

Acute mesenteric ischemia (AMI) is a severe and life-threatening condition with a mortality rate of up to 50%. Its treatment, which depends on the etiology, focuses on preserving intestinal viability through prompt restoration of blood flow. Although it is well established that intestinal ischemia-reperfusion results in significant local tissue damage, it is less recognized that it can also lead to remote tissue injuries, particularly in the lungs. Acute lung injury following intestinal ischemia-reperfusion is a severe complication that affects nearly 30% of patients with acute mesenteric ischemia and significantly contributes to mortality. The underlying pathophysiology of this injury is complex and multifactorial, yet it remains poorly understood. Neutrophil-endothelial interactions, regulated by both systemic and local mediators, play a pivotal role. Among the contributing factors, the intestinal ischemia-reperfusion process itself appears to be the most significant. Reperfusion of the ischemic intestine allows the release of mediators generated during ischemia into the systemic circulation. This triggers a cascade of biological events, including elevated levels of proinflammatory cytokines, overproduction of reactive oxygen species (ROS), nitric oxide imbalance, neutrophil activation, mitochondrial damage, and the initiation of cell death pathways. Here, we review the current knowledge on the various pathophysiological pathways explored in clinical and animal models of acute lung injury induced by intestinal ischemia-reperfusion, with the aim of providing therapeutic insights.

Session I of the inaugural biennial Research Symposium on Pulmonary Injury and Repair of the Endothelium (ReSPIRE) highlighted recent advances in endothelial bioenergetics and metabolism and their role in pulmonary vascular diseases. Emerging evidence suggests that the maladaptation of metabolic pathways in the lung endothelium contributes to the progression of the acute respiratory distress syndrome (ARDS) and pulmonary arterial hypertension (PAH). The conference highlighted several new aspects of endothelial metabolism, including the use of alternative fuel sources such as fructose and fatty acids, inflammatory signaling mediated by mitochondrial depolarization, bioenergetic reprogramming through isoform switching of genes during hypoxia, and feedback regulation of metabolism by hypercapnia. Ultimately, these findings point to future research directions aimed at identifying mechanisms of dysregulated endothelial metabolism, which could serve as therapeutic targets for pulmonary vascular diseases.