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Impact of thrombosis on pulmonary endothelial injury and repair following sepsis
The prevailing morbidity and mortality in sepsis are largely due to multiple organ dysfunction (MOD), most commonly lung injury, as well as renal and cardiac dysfunction. Despite recent advances in defining many aspects of the pathogenesis of sepsis-related MOD, including acute respiratory distress syndrome (ARDS), there are currently no effective pharmacological or cell-based treatments for the disease. Human and animal studies have shown that pulmonary thrombosis is common in sepsis-induced ARDS, and preclinical studies have shown that anticoagulation may improve outcome following sepsis challenge. The potential benefici...
Source: AJP: Lung Cellular and Molecular Physiology - April 1, 2017 Category: Respiratory Medicine Authors: Evans, C. E., Zhao, Y.-Y. Tags: REVIEW Source Type: research

Alcohol drives S-nitrosylation and redox activation of protein phosphatase 1, causing bovine airway cilia dysfunction
Individuals with alcohol (ethanol)-use disorders are at increased risk for lung infections, in part, due to defective mucociliary clearance driven by motile cilia in the airways. We recently reported that isolated, demembranated bovine cilia (axonemes) are capable of producing nitric oxide (•NO) when exposed to biologically relevant concentrations of alcohol. This increased presence of •NO can lead to protein S-nitrosylation, a posttranslational modification signaling mechanism involving reversible adduction of nitrosonium cations or •NO to thiolate or thiyl radicals, respectively, of proteins forming S-nitr...
Source: AJP: Lung Cellular and Molecular Physiology - March 9, 2017 Category: Respiratory Medicine Authors: Price, M. E., Pavlik, J. A., Liu, M., Ding, S.-J., Wyatt, T. A., Sisson, J. H. Tags: RAPID REPORT Source Type: research

Heterogeneity of airway wall dimensions in humans: a critical determinant of lung function in asthmatics and nonasthmatics
Airway remodeling, a key feature of asthma, alters every layer of the airway wall but most strikingly the airway smooth muscle (ASM) layer. Airway remodeling in asthmatics contributes to fixed airflow obstruction and can amplify airway narrowing caused by ASM activation. Previous modeling studies have shown that the increase in ASM mass has the largest effect on increasing maximal airway narrowing. Simulated heterogeneity in the dimensions and properties of the airway wall can further amplify airway narrowing. Using measurements made on histological sections from donor lungs, we show for the first time that there is profou...
Source: AJP: Lung Cellular and Molecular Physiology - March 9, 2017 Category: Respiratory Medicine Authors: Pascoe, C. D., Seow, C. Y., Hackett, T. L., Pare, P. D., Donovan, G. M. Tags: RESEARCH ARTICLE Source Type: research

miR-34a promotes fibrosis in aged lungs by inducing alveolarepithelial dysfunctions
In this study, by using a lung fibrosis model established in old mice, we found that ablation of miR-34a protected aged animals from developing experimental lung fibrosis. miR-34a was upregulated in lung epithelial cells, but not in lung fibroblasts of aged mice, and miR-34a expression was further increased in epithelial cells of the fibrotic lungs of these old animals. We found that miR-34a induced dysfunctions in alveolar epithelial cells (AECs), as evidenced by increased cellular senescence and apoptosis and mitochondrial aberrations. More importantly, these abnormalities were attenuated in AECs of the fibrotic lungs of...
Source: AJP: Lung Cellular and Molecular Physiology - March 9, 2017 Category: Respiratory Medicine Authors: Cui, H., Ge, J., Xie, N., Banerjee, S., Zhou, Y., Liu, R.-M., Thannickal, V. J., Liu, G. Tags: RESEARCH ARTICLE Source Type: research

Sex-specific effects of sex steroids on alveolar epithelial Na+ transport
In conclusion, female sex steroids stimulate Na+ transport especially in females and prevent the inhibitory effect of DHT in males. The ineffectiveness of testosterone suggests that Na+ transport is largely unaffected by androgens. Thus, the higher responsiveness of female cells to female sex steroids explains the higher Na+ transport activity, possibly leading to a functional advantage in females. (Source: AJP: Lung Cellular and Molecular Physiology)
Source: AJP: Lung Cellular and Molecular Physiology - March 9, 2017 Category: Respiratory Medicine Authors: Haase, M., Laube, M., Thome, U. H. Tags: RESEARCH ARTICLE Source Type: research

Sialic acid-to-urea ratio as a measure of airway surface hydration
Although airway mucus dehydration is key to pathophysiology of cystic fibrosis (CF) and other airways diseases, measuring mucus hydration is challenging. We explored a robust method to estimate mucus hydration using sialic acid as a marker for mucin content. Terminal sialic acid residues from mucins were cleaved by acid hydrolysis from airway samples, and concentrations of sialic acid, urea, and other biomarkers were analyzed by mass spectrometry. In mucins purified from human airway epithelial (HAE), sialic acid concentrations after acid hydrolysis correlated with mucin concentrations (r2 = 0.92). Sialic acid-to-urea rati...
Source: AJP: Lung Cellular and Molecular Physiology - March 9, 2017 Category: Respiratory Medicine Authors: Esther, C. R., Hill, D. B., Button, B., Shi, S., Jania, C., Duncan, E. A., Doerschuk, C. M., Chen, G., Ranganathan, S., Stick, S. M., Boucher, R. C. Tags: RESEARCH ARTICLE Source Type: research

Leonardo da Vinci: engineer, bioengineer, anatomist, and artist
Leonardo da Vinci (1452–1519) enjoys a reputation as one of the most talented people of all time in the history of science and the arts. However, little attention has been given to his contributions to physiology. One of his main interests was engineering, and he was fascinated by structural problems and the flow patterns of liquids. He also produced a large number of ingenious designs for warfare and a variety of highly original flying machines. But of particular interest to us are his contributions to bioengineering and how he used his knowledge of basic physical principles to throw light on physiological function....
Source: AJP: Lung Cellular and Molecular Physiology - March 9, 2017 Category: Respiratory Medicine Authors: West, J. B. Tags: HISTORICAL ARTICLE Source Type: research

Plasma membrane wounding and repair in pulmonary diseases
Various pathophysiological conditions such as surfactant dysfunction, mechanical ventilation, inflammation, pathogen products, environmental exposures, and gastric acid aspiration stress lung cells, and the compromise of plasma membranes occurs as a result. The mechanisms necessary for cells to repair plasma membrane defects have been extensively investigated in the last two decades, and some of these key repair mechanisms are also shown to occur following lung cell injury. Because it was theorized that lung wounding and repair are involved in the pathogenesis of acute respiratory distress syndrome (ARDS) and idiopathic pu...
Source: AJP: Lung Cellular and Molecular Physiology - March 9, 2017 Category: Respiratory Medicine Authors: Cong, X., Hubmayr, R. D., Li, C., Zhao, X. Tags: REVIEW Source Type: research

Long-acting {beta}2-agonists promote glucocorticoid-mediated repression of NF-{kappa}B by enhancing expression of the feedback regulator TNFAIP3
Glucocorticoids, or corticosteroids, are effective treatments for many chronic inflammatory diseases, and in mild/moderate asthma, long-acting β2-adrenoceptor agonists (LABAs) enhance the efficacy of inhaled corticosteroids (ICSs) more than increasing the ICS dose. In human bronchial epithelial, BEAS-2B, cells, expression of TNFα-induced protein-3 (TNFAIP3), or A20, a dual-ubiquitin ligase that provides feedback inhibition of NF-B, was induced by budesonide, an ICS, and formoterol, a LABA, and was further enhanced by budesonide-formoterol combination. The proinflammatory cytokine TNF induced TNFAIP3 and TNF expr...
Source: AJP: Lung Cellular and Molecular Physiology - February 28, 2017 Category: Respiratory Medicine Authors: Altonsy, M. O., Mostafa, M. M., Gerber, A. N., Newton, R. Tags: RESEARCH ARTICLE Source Type: research

Airway smooth muscle tone increases airway responsiveness in healthy young adults
The objective of the present study was to assess the effect of tone on airway responsiveness in humans. Ten healthy volunteers underwent methacholine challenge on two occasions. One challenge consisted of six serial doses of saline followed by a single high dose of methacholine. The other consisted of six low doses of methacholine 5 min apart followed by a higher dose. The cumulative dose was identical for both challenges. After both methacholine challenges, subjects took a deep inspiration (DI) to total lung capacity as another way to probe ASM mechanics. Responses to methacholine and the DI were measured using a multifre...
Source: AJP: Lung Cellular and Molecular Physiology - February 28, 2017 Category: Respiratory Medicine Authors: Gazzola, M., Lortie, K., Henry, C., Mailhot-Larouche, S., Chapman, D. G., Couture, C., Seow, C. Y., Pare, P. D., King, G. G., Boulet, L.-P., Bosse, Y. Tags: RESEARCH ARTICLE Source Type: research

Targeted epigenetic editing of SPDEF reduces mucus production in lung epithelial cells
This study aims to reduce lung epithelial mucus production by targeted silencing SPDEF using the novel strategy, epigenetic editing. Zinc fingers and CRISPR/dCas platforms were engineered to target repressors (KRAB, DNA methyltransferases, histone methyltransferases) to the SPDEF promoter. All constructs were able to effectively suppress both SPDEF mRNA and protein expression, which was accompanied by inhibition of downstream mucus-related genes [anterior gradient 2 (AGR2), mucin 5AC (MUC5AC)]. For the histone methyltransferase G9A, and not its mutant or other effectors, the obtained silencing was mitotically stable. These...
Source: AJP: Lung Cellular and Molecular Physiology - February 28, 2017 Category: Respiratory Medicine Authors: Song, J., Cano-Rodriquez, D., Winkle, M., Gjaltema, R. A. F., Goubert, D., Jurkowski, T. P., Heijink, I. H., Rots, M. G., Hylkema, M. N. Tags: RESEARCH ARTICLE Source Type: research

Activation of bitter taste receptors in pulmonary nociceptors sensitizes TRPV1 channels through the PLC and PKC signaling pathway
Bitter taste receptors (T2Rs), a G protein-coupled receptor family capable of detecting numerous bitter-tasting compounds, have recently been shown to be expressed and play diverse roles in many extraoral tissues. Here we report the functional expression of T2Rs in rat pulmonary sensory neurons. In anesthetized spontaneously breathing rats, intratracheal instillation of T2R agonist chloroquine (10 mM, 0.1 ml) significantly augmented chemoreflexes evoked by right-atrial injection of capsaicin, a specific activator for transient receptor potential vanilloid receptor 1 (TRPV1), whereas intravenous infusion of chloroquine fail...
Source: AJP: Lung Cellular and Molecular Physiology - February 28, 2017 Category: Respiratory Medicine Authors: Gu, Q., Joe, D. S., Gilbert, C. A. Tags: RESEARCH ARTICLE Source Type: research

Capsaicin-induced Ca2+ signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH
In this study, we observed that a capsaicin-induced increase in [Ca2+]cyt was significantly enhanced in PASMCs from patients with idiopathic pulmonary arterial hypertension (IPAH) compared with normal PASMCs from healthy donors. In addition, the protein expression level of TRPV1 in IPAH PASMCs was greater than in normal PASMCs. Increasing the temperature from 23 to 43°C, or decreasing the extracellular pH value from 7.4 to 5.9 enhanced capsaicin-induced increases in [Ca2+]cyt; the acidity (pH 5.9)- and heat (43°C)-mediated enhancement of capsaicin-induced [Ca2+]cyt increases were greater in IPAH PASMCs than in norm...
Source: AJP: Lung Cellular and Molecular Physiology - February 28, 2017 Category: Respiratory Medicine Authors: Song, S., Ayon, R. J., Yamamura, A., Yamamura, H., Dash, S., Babicheva, A., Tang, H., Sun, X., Cordery, A. G., Khalpey, Z., Black, S. M., Desai, A. A., Rischard, F., McDermott, K. M., Garcia, J. G. N., Makino, A., Yuan, J. X.- J. Tags: RESEARCH ARTICLE Source Type: research

Dysregulated Nox4 ubiquitination contributes to redox imbalance and age-related severity of acute lung injury
Acute respiratory distress syndrome (ARDS) is a devastating critical illness disproportionately affecting the elderly population, with both higher incidence and mortality. The integrity of the lung endothelial cell (EC) monolayer is critical for preservation of lung function. However, mechanisms mediating EC barrier regulation in the context of aging remain unclear. We assessed the severity of acute lung injury (ALI) in young (2 mo) and aged (18 mo) mice using a two-hit preclinical model. Compared with young cohorts, aged mice exhibited increased ALI severity, with greater vascular permeability characterized by elevated al...
Source: AJP: Lung Cellular and Molecular Physiology - February 28, 2017 Category: Respiratory Medicine Authors: Palumbo, S., Shin, Y.-J., Ahmad, K., Desai, A. A., Quijada, H., Mohamed, M., Knox, A., Sammani, S., Colson, B. A., Wang, T., Garcia, J. G. N., Hecker, L. Tags: RESEARCH ARTICLE Source Type: research

Novel applications for a noninvasive sampling method of the nasal mucosa
In this study, we optimize and validate a novel methodology using absorbent Leukosorb paper cut to fit the nasal passage to extract epithelial lining fluid (ELF) from the nasal mucosa. The ELF sampling method limits the dilution of soluble mediators, allowing quantification of both high- and low-abundance soluble biomarkers such as IL-1β, IL-8, IL-6, interferon gamma-induced protein 10 (IP-10), and neutrophil elastase. Additionally, we demonstrate that this method can successfully detect the presence of respiratory pathogens such as influenza virus and markers of antibiotic-resistant bacteria in the nasal mucosa. Effi...
Source: AJP: Lung Cellular and Molecular Physiology - February 7, 2017 Category: Respiratory Medicine Authors: Rebuli, M. E., Speen, A. M., Clapp, P. W., Jaspers, I. Tags: INNOVATIVE METHODOLOGY Source Type: research