scholarly journals Low Dose Hyperoxia Primes Airways for Fibrosis in Mice after Influenza A Infection

2020 ◽  
Author(s):  
Andrew M. Dylag ◽  
Jeannie Haak ◽  
Rachel Warren ◽  
Min Yee ◽  
Gloria S. Pryhuber ◽  
...  
Keyword(s):  
Lung Function ◽  
Viral Infection ◽  
Preterm Infants ◽  
Influenza A ◽  
Low Dose ◽  
Viral Infections ◽  
Airway Hyperreactivity ◽  
Normal Lung ◽  
High Dose ◽  
Neonatal Hyperoxia

AbstractIt is well known that supplemental oxygen used to treat preterm infants in respiratory distress is associated with permanently disrupting lung development and the host response to influenza A virus (IAV). However, many infants who go home with normally functioning lungs are also at risk for hyperreactivity after a respiratory viral infection suggesting neonatal oxygen may have induced hidden molecular changes that may prime to the lung for disease. We discovered that thrombospondin-1 (TSP-1) is elevated in adult mice exposed to high-dose neonatal hyperoxia that is known to cause alveolar simplification and fibrotic lung disease following IAV infection. TSP-1 was also elevated in a new, low-dose hyperoxia mouse model (40% for 8 days; 40×8) that we recently reported causes a transient change in lung function that resolves by 8 weeks of age. Elevated TSP-1 was also identified in human autopsy samples of BPD-affected former preterm infants. Consistent with TSP-1 being a master TGFβ regulator, an early transient activation of TGFβ signaling, increased airway hyperreactivity, and peribronchial inflammation and fibrosis were seen when 40×8 mice were infected with IAV, which was not seen in infected room air controls. These findings reveal low dose of neonatal hyperoxia that does not affect lung function or structure may still change expression of genes, such as TSP-1, that may prime the lung for disease following respiratory viral infections, and may help explain why former preterm infants who have normal lung function are susceptible to airway obstruction and increased morbidity after viral infection.

scholarly journals Low Dose Hyperoxia Primes Airways for Fibrosis in Mice after Influenza A Infection

2021 ◽  
Author(s):  
Andrew M Dylag ◽  
Jeannie Haak ◽  
Rachel Warren ◽  
Min Yee ◽  
Gloria S Pryhuber ◽  
...  
Keyword(s):  
Lung Function ◽  
Viral Infection ◽  
Preterm Infants ◽  
Influenza A ◽  
Low Dose ◽  
Supplemental Oxygen ◽  
Airway Hyperreactivity ◽  
Normal Lung ◽  
Tgfβ Signaling ◽  
Transient Activation

It is well known that supplemental oxygen used to treat preterm infants in respiratory distress is associated with permanently disrupting lung development and the host response to influenza A virus (IAV). However, many infants who go home with normally functioning lungs are also at risk for hyperreactivity after a respiratory viral infection. We recently reported a new, low-dose hyperoxia mouse model (40% for 8 days; 40x8) that causes a transient change in lung function that resolves, rendering 40x8 adult animals functionally indistinguishable from room air controls. Here we reported that when infected with IAV, 40x8 mice display an early transient activation of TGFβ signaling and later airway hyperreactivity associated with peribronchial inflammation (profibrotic macrophages) and fibrosis compared to infected room air controls, suggesting neonatal oxygen induced hidden molecular changes that prime the lung for hyperreactive airways disease. While searching for potential activators of TGFβ signaling, we discovered that thrombospondin-1 (TSP-1) is elevated in naïve 40x8 mice compared to controls and localized to lung megakaryocytes and platelets before and during IAV infection. Elevated TSP-1 was also identified in human autopsy samples of former preterm infants with bronchopulmonary dysplasia. These findings reveal how low doses of oxygen that do not durably change lung function may prime it for hyperreactive airways disease by changing expression of genes, such as TSP-1, thus helping to explain why former preterm infants who have normal lung function are susceptible to airway obstruction and increased morbidity after viral infection.

scholarly journals Differential susceptibility of inbred mouse strains to chlorine-induced airway fibrosis

2013 ◽  
Vol 304 (2) ◽  
pp. L92-L102 ◽  
Author(s):  
Yiqun Mo ◽  
Jing Chen ◽  
Connie F. Schlueter ◽  
Gary W. Hoyle
Keyword(s):  
Lung Function ◽  
Lung Injury ◽  
Airway Disease ◽  
Airway Hyperreactivity ◽  
Normal Lung ◽  
High Dose ◽  
Epithelial Repair ◽  
Keratin 5 ◽  
Normal Lung Function ◽  
Airway Fibrosis

Chlorine is a reactive gas that is considered a chemical threat agent. Humans who develop acute lung injury from chlorine inhalation typically recover normal lung function; however, a subset can experience chronic airway disease. To examine pathological changes following chlorine-induced lung injury, mice were exposed to a single high dose of chlorine, and repair of the lung was analyzed at multiple times after exposure. In FVB/NJ mice, chlorine inhalation caused pronounced fibrosis of larger airways that developed by day 7 after exposure and was associated with airway hyperreactivity. In contrast, A/J mice had little or no airway fibrosis and had normal lung function at day 7. Unexposed FVB/NJ mice had less keratin 5 staining (basal cell marker) than A/J mice in large intrapulmonary airways where epithelial repair was poor and fibrosis developed after chlorine exposure. FVB/NJ mice had large areas devoid of epithelium on day 1 after exposure leading to fibroproliferative lesions on days 4 and 7. A/J mice had airways covered by squamous keratin 5-stained cells on day 1 that transitioned to a highly proliferative reparative epithelium by day 4 followed by the reappearance of ciliated and Clara cells by day 7. The data suggest that lack of basal cells in the large intrapulmonary airways and failure to effect epithelial repair at these sites are factors contributing to the development of airway fibrosis in FVB/NJ mice. The observed differences in susceptibility to chlorine-induced airway disease provide a model in which mechanisms and treatment of airway fibrosis can be investigated.

scholarly journals DNA methylation is associated with airflow obstruction in patients living with HIV

Thorax ◽  
2020 ◽  
pp. thoraxjnl-2020-215866
Author(s):  
Ana I Hernandez Cordero ◽  
Chen Xi Yang ◽  
Maen Obeidat ◽  
Julia Yang ◽  
Julie MacIsaac ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Lung Function ◽  
Viral Infections ◽  
Airflow Obstruction ◽  
Normal Lung ◽  
People Living With Hiv ◽  
Global Methylation ◽  
Age Related ◽  
Impaired Lung Function ◽  
Living With Hiv

IntroductionPeople living with HIV (PLWH) suffer from age-related comorbidities such as COPD. The processes responsible for reduced lung function in PLWH are largely unknown. We performed an epigenome-wide association study to investigate whether blood DNA methylation is associated with impaired lung function in PLWH.MethodsUsing blood DNA methylation profiles from 161 PLWH, we tested the effect of methylation on FEV1, FEV1/FVC ratio and FEV1 decline over a median of 5 years. We evaluated the global methylation of PLWH with airflow obstruction by testing the differential methylation of transposable elements Alu and LINE-1, a well-described marker of epigenetic ageing.ResultsAirflow obstruction as defined by a FEV1/FVC<0.70 was associated with 1393 differentially methylated positions (DMPs), while 4676 were associated with airflow obstruction based on the FEV1/FVC<lower limit of normal. These DMPs were enriched for biological pathways associated with chronic viral infections. The airflow obstruction group was globally hypomethylated compared with those without airflow obstruction. 103 and 7112 DMPs were associated with FEV1 and FEV1/FVC, respectively. No positions were associated with FEV1 decline.ConclusionA large number of DMPs were associated with airflow obstruction and lung function in a unique cohort of PLWH. Airflow obstruction in even relatively young PLWH is associated with global hypomethylation, suggesting advanced epigenetic ageing compared with those with normal lung function. The disturbance of the epigenetic regulation of key genes not previously identified in non-HIV COPD cohorts could explain the unique risk of COPD in PLWH.

scholarly journals Activation Status Dictates the Function of Unlicensed Natural Killer Cells

2021 ◽  
Author(s):  
Ethan G Aguilar ◽  
Cordelia Dunai ◽  
Sean J. Judge ◽  
Anthony Elston Zamora ◽  
Lam T. Khuat ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Viral Infections ◽  
Nk Cell ◽  
T Cell Response ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Innate Defense ◽  
Activation Status

Natural Killer (NK) cells are involved in innate defense against viral infection and cancer. NK cells can be divided into subsets based on the ability of different receptors to bind to major histocompatibility (MHC) class I molecules resulting in differential responses upon activation in a process called "licensing" or "arming". NK cells expressing receptors that bind self-MHC are considered licensed due to augmented effector lytic function capability compared to unlicensed subsets. However, we demonstrated unlicensed NK subsets instead positively regulate the adaptive T cell response during viral infections due to localization and cytokine production. We demonstrate here that the differential effects of the two types of NK subsets is contingent on the environment using viral infection and hematopoietic stem cell transplantation (HSCT) models. Infection of mice with high-dose (HD) MCMV leads to a loss of licensing-associated differences as compared to mice with low-dose infection, as the unlicensed NK subset no longer localized in lymph nodes (LN), but instead remained at the site of infection. Similarly, the patterns observed during HD infection paralleled with the phenotypes of both human and mouse NK cells in a HSCT setting where NK cells exhibit an activated phenotype. However, in contrast to effects of subset depletion in T-replete models, the licensed NK cell subsets still dominated anti-viral responses post-HSCT. Overall, our results highlight the intricate tuning of the NK cells and how it impacts overall immune responses with regard to licensing patterns, as it is dependent on the level of stimulation and their activation status.

Lung function of preterm infants before and after viral infections

2014 ◽  
Vol 173 (11) ◽  
pp. 1497-1504 ◽  
Author(s):  
Simon B. Drysdale ◽  
Jessica Lo ◽  
Michael Prendergast ◽  
Mireia Alcazar ◽  
Theresa Wilson ◽  
...  
Keyword(s):  
Lung Function ◽  
Preterm Infants ◽  
Viral Infections ◽  
Before And After

scholarly journals SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties

2021 ◽  
Vol 11 ◽  
Author(s):  
Alastair Watson ◽  
Jens Madsen ◽  
Howard William Clark
Keyword(s):  
Viral Infection ◽  
Influenza A ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Chronic Obstructive ◽  
Cell Functions ◽  
Increased Risk ◽  
Syncytial Virus

Surfactant proteins A (SP-A) and D (SP-D) are soluble innate immune molecules which maintain lung homeostasis through their dual roles as anti-infectious and immunomodulatory agents. SP-A and SP-D bind numerous viruses including influenza A virus, respiratory syncytial virus (RSV) and human immunodeficiency virus (HIV), enhancing their clearance from mucosal points of entry and modulating the inflammatory response. They also have diverse roles in mediating innate and adaptive cell functions and in clearing apoptotic cells, allergens and other noxious particles. Here, we review how the properties of these first line defense molecules modulate inflammatory responses, as well as host-mediated immunopathology in response to viral infections. Since SP-A and SP-D are known to offer protection from viral and other infections, if their levels are decreased in some disease states as they are in severe asthma and chronic obstructive pulmonary disease (COPD), this may confer an increased risk of viral infection and exacerbations of disease. Recombinant molecules of SP-A and SP-D could be useful in both blocking respiratory viral infection while also modulating the immune system to prevent excessive inflammatory responses seen in, for example, RSV or coronavirus disease 2019 (COVID-19). Recombinant SP-A and SP-D could have therapeutic potential in neutralizing both current and future strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus as well as modulating the inflammation-mediated pathology associated with COVID-19. A recombinant fragment of human (rfh)SP-D has recently been shown to neutralize SARS-CoV-2. Further work investigating the potential therapeutic role of SP-A and SP-D in COVID-19 and other infectious and inflammatory diseases is indicated.

Altered expression and in vivo lung function of protease-activated receptors during influenza A virus infection in mice

2004 ◽  
Vol 286 (2) ◽  
pp. L388-L398 ◽  
Author(s):  
Rommel S. Lan ◽  
Geoffrey A. Stewart ◽  
Roy G. Goldie ◽  
Peter J. Henry
Keyword(s):  
Lung Function ◽  
Viral Infection ◽  
Influenza A ◽  
Airway Disease ◽  
Protease Activated Receptors ◽  
Altered Expression ◽  
Agonist Peptide ◽  
Tracheal Epithelial Cells ◽  
And Function

Protease-activated receptors (PARs) are widely distributed in human airways, and recent evidence indicates a role for PARs in the pathophysiology of inflammatory airway disease. To further investigate the role of PARs in airway disease, we determined the expression and function of PARs in a murine model of respiratory tract viral infection. PAR-1, PAR-2, PAR-3, and PAR-4 mRNA and protein were expressed in murine airways, and confocal microscopy revealed colocalization of PAR-2 and cyclooxygenase (COX)-2 immunostaining in basal tracheal epithelial cells. Elevated levels of PAR immunostaining, which was particularly striking for PAR-1 and PAR-2, were observed in the airways of influenza A/PR-8/34 virus-infected mice compared with sham-infected mice. Furthermore, increased PAR-1 and PAR-2 expression was associated with significant changes in in vivo lung function responses. PAR-1 agonist peptide potentiated methacholine-induced increases in airway resistance in anesthetized sham-infected mice (and in indomethacin-treated, virus-infected mice), but no such potentiation was observed in virus-infected mice. PAR-2 agonist peptide transiently inhibited methacholine-induced bronchoconstriction in sham-infected mice, and this effect was prolonged in virus-infected mice. These findings suggest that during viral infection, the upregulation of PARs in the airways is coupled to increased activation of COX and enhanced generation of bronchodilatory prostanoids.

scholarly journals P50 Individual variations in fentanyl pharmacokinetics and pharmacodynamics in preterm infants

2019 ◽  
Vol 104 (6) ◽  
pp. e37.3-e38
Author(s):  
J Kindblom ◽  
E Norman ◽  
A Rane ◽  
A-C Berg ◽  
U Schubert ◽  
...  
Keyword(s):  
Preterm Infants ◽  
Low Dose ◽  
Volume Of Distribution ◽  
High Dose ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Pain Scores ◽  
Individual Variations ◽  
Physiologic Parameters ◽  
New Formulation ◽  
Study Inclusion

BackgroundFentanyl pharmacokinetics and pharmacodynamics are lacking in preterm infants. Our aim was to study these and their relation with a new formulation of fentanyl 5 mg/mL for procedural pain.MethodsPreterm infants were given 0.5 (n=20, median gestational age 26.5; range 23.3–34.1 weeks) and 2 mg/kg (n=8, 27.4; 25.3–30.7 weeks) fentanyl, respectively, before skin-breaking procedures or tracheal intubation. Blood samples were collected after ten minutes, two, four, eight and 24 hours. Physiologic parameters were monitored and pain scores assessed.ResultsThe median fentanyl concentrations were 0.18, 0.15, 0.15 and 0.57, 0.37, 0.35ng/mL at 15–31 minutes, two and four hours and the half-lives were 1.6 to 20.5 or 4.1 to 32.6 hours for the low and high dose groups, respectively. A significant correlation was seen between weight at study inclusion and half-life (Spearman´s r = -0.9, p< 0.001), volume of distribution (r = -0.8, p < 0.01) and clearance (r = -0.9, p < 0.01) in the low dose group (n=9). Pain assessment results were not correlated to pharmacokinetic variables. Fentanyl was well tolerated.ConclusionThe inter-individual variation of fentanyl pharmacokinetics is large in preterm infants and the dose of 0.5 mg/kg seems too small for skin-breaking procedures.Disclosure(s)Nothing to disclose

scholarly journals Fucoidan and Lung Function: Value in Viral Infection

Marine Drugs ◽  
2020 ◽  
Vol 19 (1) ◽  
pp. 4
Author(s):  
J. Helen Fitton ◽  
Ah Young Park ◽  
Samuel S. Karpiniec ◽  
Damien N. Stringer
Keyword(s):  
Innate Immunity ◽  
Lung Function ◽  
Viral Infection ◽  
Animal Studies ◽  
Viral Infections ◽  
Short Review ◽  
Lung Damage ◽  
Acute Viral Infection ◽  
Pulmonary Damage

Compromised lung function is a feature of both infection driven and non-infective pathologies. Viral infections—including the current pandemic strain SARS-CoV-2—that affect lung function can cause both acute and long-term chronic damage. SARS-CoV-2 infection suppresses innate immunity and promotes an inflammatory response. Targeting these aspects of SARS-CoV-2 is important as the pandemic affects greater proportions of the population. In clinical and animal studies, fucoidans have been shown to increase innate immunity and decrease inflammation. In addition, dietary fucoidan has been shown to attenuate pulmonary damage in a model of acute viral infection. Direct inhibition of SARS-CoV-2 in vitro has been described, but is not universal. This short review summarizes the current research on fucoidan with regard to viral lung infections and lung damage.

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