scholarly journals Mitogenic stimulation accelerates influenza-induced mortality by increasing susceptibility of alveolar type II cells to infection

2017 ◽  
Vol 114 (32) ◽  
pp. E6613-E6622 ◽  
Author(s):  
Nikolaos M. Nikolaidis ◽  
John G. Noel ◽  
Lori B. Pitstick ◽  
Jason C. Gardner ◽  
Yasuaki Uehara ◽  
...  
Keyword(s):  
Viral Infection ◽  
Influenza A ◽  
Ex Vivo ◽  
Keratinocyte Growth Factor ◽  
Alveolar Epithelium ◽  
Host Susceptibility ◽  
Alveolar Type ◽  
Type Ii ◽  
Mitogenic Stimulation

Development of pneumonia is the most lethal consequence of influenza, increasing mortality more than 50-fold compared with uncomplicated infection. The spread of viral infection from conducting airways to the alveolar epithelium is therefore a pivotal event in influenza pathogenesis. We found that mitogenic stimulation with keratinocyte growth factor (KGF) markedly accelerated mortality after infectious challenge with influenza A virus (IAV). Coadministration of KGF with IAV markedly accelerated the spread of viral infection from the airways to alveoli compared with challenge with IAV alone, based on spatial and temporal analyses of viral nucleoprotein staining of lung tissue sections and dissociated lung cells. To better define the temporal relationship between KGF administration and susceptibility to IAV infection in vivo, we administered KGF 120, 48, 24, and 0 h before intrapulmonary IAV challenge and assessed the percentages of proliferating and IAV-infected, alveolar type II (AECII) cells in dispersed lung cell populations. Peak AECII infectivity coincided with the timing of KGF administration that also induced peak AECII proliferation. AECII from mice that were given intrapulmonary KGF before isolation and then infected with IAV ex vivo exhibited the same temporal pattern of proliferation and infectious susceptibility. KGF-induced increases in mortality, AECII proliferation, and enhanced IAV susceptibility were all reversed by pretreatment of the animals with the mTOR inhibitor rapamycin before mitogenic stimulation. Taken together, these data suggest mTOR signaling-dependent, mitogenic conditioning of AECII is a determinant of host susceptibility to infection with IAV.

Inhibition of alveolar type II cell ATP and surfactant synthesis by nitric oxide

1996 ◽  
Vol 270 (6) ◽  
pp. L898-L906 ◽  
Author(s):  
I. Y. Haddad ◽  
S. Zhu ◽  
J. Crow ◽  
E. Barefield ◽  
T. Gadilhe ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Synthesis ◽  
Alveolar Epithelium ◽  
Alveolar Type ◽  
Type Ii ◽  
Surfactant Synthesis ◽  
Cell Energy ◽  
Type Ii Cell

Alveolar type II (ATII) cells, are often exposed to increased concentration of endogenous and exogenous nitric oxide (.NO). Exposure of freshly isolated rat ATII cells for 2 h to 1-3 microM .NO, generated by S-nitroso-N-penicillamine (SNAP), spermine NONOate, or 3-morpholino-sydnonimine (SIN-1) in the presence of superoxide dismutase, resulted in approximately 60% decrease in the rate of surfactant synthesis, as measured by the rate of incorporation of [methyl-3H]choline into phosphatidylcholine, and 60-80% inhibition of cellular ATP levels, as determined by bioluminescence. Similar results were obtained after incubation of ATII cells with authentic peroxynitrite (0.5 mM) but not SIN-1, a putative generator of peroxynitrite. Addition into the medium of oxyhemoglobin (20 microM), which scavenged .NO, or enhancement of ATII glutathione levels by preincubation with glutathione ester (5 mM) totally prevented the NONOate (100 microM) inhibition of cellular ATP. In contrast to the in vitro findings, normal levels of ATP and lipid synthesis were measured in ATII cells isolated from the lungs of rats that breathed .NO gas (80 ppm) in 21% O2 for 2 h (n = 4). This lack of effect may be due either to the presence of various antioxidants (such as glutathione) in the epithelial lining fluid or to the relatively low concentrations of .NO reaching the alveolar epithelium. We conclude that .NO and peroxynitrite, at concentrations likely to be encountered in vivo during inflammation, decrease ATII cell energy stores and surfactant synthesis, which may lead to derangement of important physiological functions.

scholarly journals Alveolar Type II Epithelial Cells Contribute to the Anti-Influenza A Virus Response in the Lung by Integrating Pathogen- and Microenvironment-Derived Signals

mBio ◽  
2016 ◽  
Vol 7 (3) ◽  
Author(s):  
S. Stegemann-Koniszewski ◽  
Andreas Jeron ◽  
Marcus Gereke ◽  
Robert Geffers ◽  
Andrea Kröger ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Epithelial Cells ◽  
Influenza A Virus ◽  
Lung Tissue ◽  
Influenza A ◽  
Ex Vivo ◽  
Type Ii ◽  
Pathogen Recognition ◽  
Cell Recruitment

ABSTRACT Influenza A virus (IAV) periodically causes substantial morbidity and mortality in the human population. In the lower lung, the primary targets for IAV replication are type II alveolar epithelial cells (AECII), which are increasingly recognized for their immunological potential. So far, little is known about their reaction to IAV and their contribution to respiratory antiviral immunity in vivo . Therefore, we characterized the AECII response during early IAV infection by analyzing transcriptional regulation in cells sorted from the lungs of infected mice. We detected rapid and extensive regulation of gene expression in AECII following in vivo IAV infection. The comparison to transcriptional regulation in lung tissue revealed a strong contribution of AECII to the respiratory response. IAV infection triggered the expression of a plethora of antiviral factors and immune mediators in AECII with a high prevalence for interferon-stimulated genes. Functional pathway analyses revealed high activity in pathogen recognition, immune cell recruitment, and antigen presentation. Ultimately, our analyses of transcriptional regulation in AECII and lung tissue as well as interferon I/III levels and cell recruitment indicated AECII to integrate signals provided by direct pathogen recognition and surrounding cells. Ex vivo analysis of AECII proved a powerful tool to increase our understanding of their role in respiratory immune responses, and our results clearly show that AECII need to be considered a part of the surveillance and effector system of the lower respiratory tract. IMPORTANCE In order to confront the health hazard posed by IAV, we need to complete our understanding of its pathogenesis. AECII are primary targets for IAV replication in the lung, and while we are beginning to understand their importance for respiratory immunity, the in vivo AECII response during IAV infection has not been analyzed. In contrast to studies addressing the response of AECII infected with IAV ex vivo , we have performed detailed gene transcriptional profiling of AECII isolated from the lungs of infected mice. Thereby, we have identified an exceptionally rapid and versatile response to IAV infection that is shaped by pathogen-derived as well as microenvironment-derived signals and aims at the induction of antiviral measures and the recruitment and activation of immune cells. In conclusion, our study presents AECII as active players in antiviral defense in vivo that need to be considered part of the sentinel and effector immune system of the lung.

cAMP activation of chloride and fluid secretion across the rabbit alveolar epithelium

1998 ◽  
Vol 275 (6) ◽  
pp. L1127-L1133 ◽  
Author(s):  
Vance G. Nielsen ◽  
Michael D. Duvall ◽  
Manuel S. Baird ◽  
Sadis Matalon
Keyword(s):  
Short Circuit ◽  
Alveolar Epithelium ◽  
Short Circuit Current ◽  
Alveolar Epithelial Cells ◽  
Alveolar Type ◽  
Intracellular Camp ◽  
Type Ii ◽  
Alveolar Fluid Clearance ◽  
Ussing Chambers

Active Na+ transport by alveolar epithelial cells has been demonstrated to contribute significantly to alveolar fluid clearance. However, the contribution of transepithelial Cl− movement to the reabsorption of isosmotic fluid across the alveolar epithelium in vivo has not been elucidated. We hypothesized that Cl− transport could be increased across the alveolar epithelium in vivo and across cultured alveolar type II cells by agents that increase intracellular cAMP (e.g., forskolin). In studies where 5% albumin in sodium methanesulfonate (a Cl−-free solution) was administered into the lung, forskolin administration significantly increased intracellular influx of Cl− and fluid into the alveolar space. In vitro studies with cultured rabbit alveolar type II cell monolayers in Ussing chambers demonstrated that elevations in intracellular cAMP increase short-circuit current by increasing both Cl−secretion and Na+ reabsorption. The cystic fibrosis transmembrane conductance regulator channel blocker glibenclamide and the loop diuretic bumetanide partially decreased the forskolin-induced increase in short-circuit current. These data may explain the failure of agonist that stimulated intracellular cAMP to increase alveolar fluid clearance in the rabbit. Moreover, the data suggest that in the event Na+absorptive pathways are damaged, transepithelial Cl− secretion and the consequent intra-alveolar fluid influx may be upregulated.

HO-1 expression in type II pneumocytes after transpulmonary gene delivery

2000 ◽  
Vol 278 (6) ◽  
pp. L1273-L1279 ◽  
Author(s):  
Yi-Hao Weng ◽  
Arthur Tatarov ◽  
Blythe P. Bartos ◽  
Christopher H. Contag ◽  
Phyllis A. Dennery
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Gene Transfer ◽  
Expression Patterns ◽  
Alveolar Epithelium ◽  
Luciferase Reporter ◽  
Heme Oxygenase 1 ◽  
Alveolar Type ◽  
Type Ii

Somatic cell gene transfer is a potentially useful strategy to alter lung function. However, achieving efficient transfer to the alveolar epithelium, especially in smaller animals, has not been demonstrated. In this study, the rat heme oxygenase-1 (HO-1) gene was delivered to the lungs of neonatal mice via transpulmonary injection. A bidirectional promoter construct coexpressing both HO-1 and a luciferase reporter gene was used so that in vivo gene expression patterns could be monitored in real time. HO-1 expression levels were also modulated with doxycycline and assessed in vivo with bioluminescent light transmitted through the tissues from the coregulated luciferase reporter. As a model of oxidative stress and HO-1-mediated protection, groups of animals were exposed to hyperoxia. After gene transfer, elevated levels of HO-1 were detected predominantly in alveolar type II cells by immunocytochemistry. With overexpression of HO-1, increased oxidative injury was observed. Furthermore, this model demonstrated a cell-specific effect of lung HO-1 overexpression in oxidative stress. Specific control of expression for therapeutic genes is possible in vivo. The transpulmonary approach may prove useful in targeting gene expression to cells of the alveolar epithelium or to circumscribed areas of the lung.

Differential Effects of Halothane and Thiopental on Surfactant Protein C Messenger RNA  In Vivo and  In Vitro in Rats 

2000 ◽  
Vol 93 (3) ◽  
pp. 805-810 ◽  
Author(s):  
Catherine Paugam-Burtz ◽  
Serge Molliex ◽  
Bernard Lardeux ◽  
Corinne Rolland ◽  
Michel Aubier ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Protein C ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Type Ii Cells ◽  
Mechanically Ventilated ◽  
Mrna Content

Background Pulmonary surfactant is a complex mixture of proteins and phospholipids synthetized by alveolar type II cells. Volatile anesthetics have been shown to reduce surfactant phospholipid biosynthesis by rat alveolar type II cells. Surfactant-associated protein C (SP-C) is critical for the alveolar surfactant functions. Our goal was to evaluate the effects of halothane and thiopental on SP-C messenger RNA (mRNA) expression in vitro in rat alveolar type II cells and in vivo in mechanically ventilated rats. Methods In vitro, freshly isolated alveolar type II cells were exposed to halothane during 4 h (1, 2, 4%) and 8 h (1%), and to thiopental during 4 h (10, 100 micrometer) and 8 h (100 micrometer). In vivo, rats were anesthetized with intraperitoneal thiopental or inhaled 1% halothane and mechanically ventilated for 4 or 8 h. SP-C mRNA expression was evaluated by ribonuclease protection assay. Results In vitro, 4-h exposure of alveolar type II cells to thiopental 10 and 100 micrometer increased their SP-C mRNA content to 145 and 197%, respectively, of the control values. In alveolar type II cells exposed for 4 h to halothane 1, 2, and 4%, the SP-C mRNA content increased dose-dependently to 160, 235, and 275%, respectively, of the control values. In vivo, in mechanically ventilated rats, 4 h of halothane anesthesia decreased the lung SP-C mRNA content to 53% of the value obtained in control (nonanesthetized, nonventilated) animals; thiopental anesthesia increased to 150% the lung SP-C mRNA content. Conclusions These findings indicate that halothane and thiopental used at clinically relevant concentrations modulate the pulmonary SP-C mRNA content in rats. In vivo, the additive role of mechanical ventilation is suggested.

scholarly journals Innate triggering and antiviral effector functions of activin A

2021 ◽  
Author(s):  
Kinda Al-Hourani ◽  
Narayan Ramamurthy ◽  
Emanuele Marchi ◽  
Ruth M Eichinger ◽  
Lian N Lee ◽  
...  
Keyword(s):  
Viral Infection ◽  
Influenza A ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Activin A ◽  
Type I ◽  
Type I Ifn ◽  
Effector Functions

First-line defence against viral infection is contingent upon rapid detection of conserved viral structural and genomic motifs by germline-encoded pattern recognition receptors, followed by activation of the type I IFN system and establishment of an intracellular antiviral state. Novel antiviral functions of bone morphogenetic protein and related activin cytokines, acting in conjunction with, and independently of, type I IFN, have recently been described. Activin A mediates multiple innate and adaptive immune functions, including antiviral effects. However, how such effects are mediated and how activin might be triggered by viral infection have not been defined. Here we addressed this in vivo and in vitro, in humans and mice. Transcriptomic analyses delineated strikingly congruent patterns of gene regulation in hepatocytes stimulated with recombinant activin A and IFNα in vitro. Activin A mRNA, encoded by INHBA, is induced upon activation of RIG-I, MDA5 and TLR7/8 viral nucleic acid sensors in vitro, across multiple cell lines and in human peripheral blood mononuclear cells. In vivo, infection of mice with influenza A also upregulated Inhba mRNA in the lung; this local upregulation of Inhba is retained in MAVS knockout mice, indicating a role for non-RIG-I-like receptors in its induction. Activin induction and signalling were also detectable in patients with chronic viral hepatitis. Together, these data suggest Activin A is triggered in parallel with type I IFN responses and can trigger related antiviral effector functions. This model has implications for the development of targeted antiviral therapies, in addition to revealing novel facets of activin biology.

Stimulation of surfactant exocytosis in primary alveolar type II cells by A. fumigatus

2020 ◽  
Author(s):  
Natalia Schiefermeier-Mach ◽  
Susanne Perkhofer ◽  
Lea Heinrich ◽  
Thomas Haller
Keyword(s):  
Pulmonary Surfactant ◽  
Defense Mechanisms ◽  
Alveolar Epithelium ◽  
Fungal Growth ◽  
Alveolar Type ◽  
Fungal Culture ◽  
Type Ii ◽  
Airborne Spores ◽  
Upper Airways ◽  
Cellular Effects

Abstract Aspergillus fumigatus is an opportunistic fungal pathogen with small airborne spores (conidia) that may escape clearance by upper airways and directly impact the alveolar epithelium. Consequently, innate alveolar defense mechanisms are being activated, including professional phagocytosis by alveolar macrophages, recruitment of circulating neutrophils and probably enhanced secretion of pulmonary surfactant by the alveolar type II (AT II) cells. However, no data are available in support of the latter hypothesis. We therefore used a coculture model of GFP-Aspergillus conidia with primary rat AT II cells and studied fungal growth, cellular Ca2+ homeostasis, and pulmonary surfactant exocytosis by live cell video microscopy. We observed all stages of fungal development, including reversible attachment, binding and internalization of conidia as well as conidial swelling, formation of germ tubes and outgrowth of hyphae. In contrast to resting conidia, which did not provoke immediate cellular effects, metabolically active conidia, fungal cellular extracts (CE) and fungal culture filtrates (CF) prepared from swollen conidia caused a Ca2+-independent exocytosis. Ca2+ signals of greatly varying delays, durations and amplitudes were observed by applying CE or CF obtained from hyphae of A. fumigatus, suggesting compounds secreted by filamentous A. fumigatus that severely interfere with AT II cell Ca2+ homeostasis. The mechanisms underlying the stimulatory effects, with respect to exocytosis and Ca2+ signaling, are unclear and need to be identified.

Sign in / Sign up

Export Citation Format

Share Document