Age-elevated prostaglandin E2 enhances mortality to influenza infection

SummaryAging impairs the immune responses to influenza A virus (IAV), resulting in increased mortality to IAV infections in older adults. With aging, there is reduced number and impaired function of alveolar macrophages (AMs), cells critical for defense against IAV. However, factors within the aged lung that impair AMs are not fully known. Using a murine model of IAV infection, we observed that aging increased the level of prostaglandin E2 (PGE2) in the bronchoalveolar lavage fluid (BALF) of aged mice compared to young mice. Blockade of the PGE2 receptor EP2 in aged mice increased AM numbers and subsequently enhanced survival to IAV. Additionally, PGE2 impaired the mitochondrial health of AMs. We also identified senescent type II alveolar epithelial cells (AECs) as a source of the aged-associated PGE2 in the lung. Our results reveal a crosstalk between AECs and AMs, via PGE2, that compromises host defense to IAV infection with aging.

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Changes in immunoreactivity for cathepsin H in rat type II alveolar epithelial cells and its proteolytic activity in bronchoalveolar lavage fluid over 24 hours

The Anatomical Record ◽

10.1002/ar.1092300411 ◽

1991 ◽

Vol 230 (4) ◽

pp. 519-523 ◽

Cited By ~ 7

Author(s):

Yukio Ishii ◽

Yutaka Hashizume ◽

Eiki Kominami ◽

Yasuo Uchiyama

Keyword(s):

Epithelial Cells ◽

Bronchoalveolar Lavage ◽

Proteolytic Activity ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Alveolar Epithelial Cells ◽

Type Ii ◽

Alveolar Epithelial ◽

Cathepsin H

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Frequency of Positive Aspergillus Tests in COVID-19 Patients in Comparison to Other Patients with Pulmonary Infections Admitted to the ICU

Journal of Clinical Microbiology ◽

10.1128/jcm.02278-20 ◽

2020 ◽

Author(s):

Erlangga Yusuf ◽

Alieke Vonk ◽

Johannes P.C. van den Akker ◽

Lonneke Bode ◽

Gregorius J. Sips ◽

...

Keyword(s):

Influenza A ◽

Pneumococcal Pneumonia ◽

Bronchoalveolar Lavage Fluid ◽

Influenza Infection ◽

Positive Culture ◽

Lavage Fluid ◽

Positive Control ◽

Community Acquired Pneumonia ◽

Respiratory Sample ◽

Test Result

The aim of this study was to describe the frequency of positive Aspergillus tests in COVID-19 patients and investigate the association between COVID-19 and a positive Aspergillus test result. We compared the proportion of positive Aspergillus tests in COVID-19 patients admitted to the ICU for > 24 hours with two control groups; patients with community acquired pneumonia with 1. a PCR confirmed influenza infection (considered as ‘positive’ control since the link between influenza and invasive aspergillosis has been established), and 2. Streptococcus pneumoniae pneumonia (in whom positive Aspergillus tests are mostly considered as colonisation). During the study period, 92 COVID-19 patients (mean age (SD) 62(14) years, 76.1% males), 48 influenza (55(14), 56.2% males), and 65 pneumococcal pneumonia (58 (15), 63,1% males) patients were identified. Any positive Aspergillus test from any respiratory sample was found in 10.9% of the COVID-19 patients, 6.2% of the patients with pneumococcal pneumonia and 22.9% of those infected with influenza. A positive culture or PCR or galactomannan test on bronchoalveolar lavage fluid (BAL) only was found in 5.4% of COVID-19 patients, which was lower than in patients with influenza (18.8%) and comparable to pneumococcal pneumonia group (4.6%). Using logistic regression analysis, the odds ratio, OR (95% CI) for a positive Aspergillus test on BAL fluid for COVID19 patients was 1.2 (0.3 to 5.1, p=0.8) compared to the pneumococcal pneumonia group while it was 0.2 (0.1 to 0.8, p=0.02) compared with influenza group. This difference remained significant when corrected for age and sex. In conclusion, in COVID19 patients, the prevalence of a positive aspergillus test was comparable to patients with admitted for pneumococcal pneumonia but substantially lower than what we observed in patients with influenza.

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Lethal H1N1 influenza A virus infection alters the murine alveolar type II cell surfactant lipidome

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00339.2016 ◽

2016 ◽

Vol 311 (6) ◽

pp. L1160-L1169 ◽

Cited By ~ 11

Author(s):

Parker S. Woods ◽

Lauren M. Doolittle ◽

Lucia E. Rosas ◽

Lisa M. Joseph ◽

Edward P. Calomeni ◽

...

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Lipid Metabolism ◽

Influenza A ◽

Bronchoalveolar Lavage Fluid ◽

Distress Syndrome ◽

Lavage Fluid ◽

Alveolar Type ◽

Type Ii ◽

Atii Cell ◽

Surfactant Lipid

Alveolar type II (ATII) epithelial cells are the primary site of influenza virus replication in the distal lung. Development of acute respiratory distress syndrome in influenza-infected mice correlates with significant alterations in ATII cell function. However, the impact of infection on ATII cell surfactant lipid metabolism has not been explored. C57BL/6 mice were inoculated intranasally with influenza A/WSN/33 (H1N1) virus (10,000 plaque-forming units/mouse) or mock-infected with virus diluent. ATII cells were isolated by a standard lung digestion protocol at 2 and 6 days postinfection. Levels of 77 surfactant lipid-related compounds of known identity in each ATII cell sample were measured by ultra-high-performance liquid chromatography-mass spectrometry. In other mice, bronchoalveolar lavage fluid was collected to measure lipid and protein content using commercial assay kits. Relative to mock-infected animals, ATII cells from influenza-infected mice contained reduced levels of major surfactant phospholipids (phosphatidylcholine, phosphatidylglycerol, and phosphatidylethanolamine) but increased levels of minor phospholipids (phosphatidylserine, phosphatidylinositol, and sphingomyelin), cholesterol, and diacylglycerol. These changes were accompanied by reductions in cytidine 5′-diphosphocholine and 5′-diphosphoethanolamine (liponucleotide precursors for ATII cell phosphatidylcholine and phosphatidylethanolamine synthesis, respectively). ATII cell lamellar bodies were ultrastructurally abnormal after infection. Changes in ATII cell phospholipids were reflected in the composition of bronchoalveolar lavage fluid, which contained reduced amounts of phosphatidylcholine and phosphatidylglycerol but increased amounts of sphingomyelin, cholesterol, and protein. Influenza infection significantly alters ATII cell surfactant lipid metabolism, which may contribute to surfactant dysfunction and development of acute respiratory distress syndrome in influenza-infected mice.

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Cysteine proteinases in bronchoalveolar epithelial cells and lavage fluid of rat lung.

Journal of Histochemistry & Cytochemistry ◽

10.1177/39.4.2005374 ◽

1991 ◽

Vol 39 (4) ◽

pp. 461-468 ◽

Cited By ~ 24

Author(s):

Y Ishii ◽

Y Hashizume ◽

T Watanabe ◽

S Waguri ◽

N Sato ◽

...

Keyword(s):

Epithelial Cells ◽

Alveolar Macrophages ◽

Cathepsin B ◽

Light And Electron Microscopy ◽

Lavage Fluid ◽

Alveolar Epithelial Cells ◽

Type Ii ◽

Mature Form ◽

Alveolar Epithelial ◽

Cathepsin H

We examined the presence of cathepsins B, H, and L in bronchoalveolar epithelial cells, including alveolar macrophages, and in bronchoalveolar lavage fluid (BALF), using immunocytochemistry and immunoblotting. By light and electron microscopy, immunoreactivity for cathepsins B, H, and L was detected in lysosomes of ciliated and non-ciliated epithelial cells of bronchi and bronchioles, and in macrophages. Immunodeposits for cathepsin H only were demonstrated in lamellar bodies of Type II alveolar epithelial cells, suggesting the cosecretion of surfactants and cathepsin H from the cells into the alveolar space. By immunoblotting, cathepsins B and H were found to be present in BALF. To further investigate the origin of these enzymes in BALF, alveolar macrophages obtained from BALF were cultured for 6 hr in a serum-free medium. Immunoblotting revealed that protein bands corresponding to the pro-form and mature form of cathepsin B and the mature form of cathepsin H were present in the culture medium. From these results, the presence of cathepsins B and H in BALF can be explained by the fact that cathepsin B is secreted from alveolar macrophages and cathepsin H is secreted mainly with surfactants from Type II cells and also from macrophages.

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Hypoxia upregulates VEGF expression in alveolar epithelial cells in vitro and in vivo

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00464.2001 ◽

2002 ◽

Vol 283 (5) ◽

pp. L1133-L1142 ◽

Cited By ~ 49

Author(s):

Isabelle Pham ◽

Tokujiro Uchida ◽

Carole Planes ◽

Lorraine B. Ware ◽

Robert Kaner ◽

...

Keyword(s):

Epithelial Cells ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Alveolar Epithelial Cells ◽

Oxygen Species ◽

Vegf Expression ◽

Vegf Mrna ◽

Alveolar Epithelial ◽

Vegf Protein

We investigated regulation of vascular endothelial growth factor (VEGF) expression by hypoxia in cultured and freshly isolated rat alveolar epithelial cells (AEC). In vitro, hypoxia increased VEGF mRNA and protein levels, with maximal stimulation at 0% O2 for 18 h. A similar upregulation of VEGF expression was found in alveolar epithelial type II (ATII) cells freshly isolated from rats exposed to 8% O2 for 24 h. In vitro , hypoxia-induced upregulation of VEGF mRNA was due to an increase in transcription, rather than an increase in RNA stability, inasmuch as the half-life of VEGF mRNA was unchanged. Upregulation of VEGF mRNA by hypoxia was mimicked by CoCl2 and desferrioxamine in normoxic AEC and was not prevented by inhibitors of reactive oxygen species, suggesting that hypoxic VEGF regulation involved an O2-dependent protein that requires ferrous ions but is independent of reactive oxygen species generation. In polarized ATII cells, VEGF protein was secreted at the apical and basolateral sides. Similarly, in rats, VEGF was secreted in bronchoalveolar lavage fluid. Hypoxia induced a twofold increase in VEGF protein at the apical side of ATII cells in culture and in bronchoalveolar lavage fluid. These findings suggest that release of VEGF synthesized by AEC may target not only endothelial cells but also other alveolar cells, including macrophages and epithelial cells.

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RIG-I Signaling via MAVS Is Dispensable for Survival in Lethal Influenza Infection In Vivo

Mediators of Inflammation ◽

10.1155/2018/6808934 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Wenxin Wu ◽

Xiaoqiu Wang ◽

Wei Zhang ◽

Lili Tian ◽

J. Leland Booth ◽

...

Keyword(s):

Immune Responses ◽

Influenza A ◽

Influenza Infection ◽

Lavage Fluid ◽

Innate Immune ◽

Innate Immune Responses ◽

Downstream Signaling ◽

Cytokine Responses

Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines. It requires interaction with an adaptor molecule, mitochondrial antiviral-signaling protein (MAVS), to activate downstream signaling pathways. To elucidate the mechanism(s) by which RIG-I-dependent recognition of IAV infection in vivo triggers innate immune responses, we infected mutant mice lacking RIG-I or MAVS with influenza A virus (IAV) and measured their innate immune responses. As has previously been demonstrated with isolated deletion of the virus recognition receptors TLR3, TLR7, and NOD2, RIG-I or MAVS knockout (KO) did not result in higher mortality and did not reduce IAV-induced cytokine responses in mice. Infected RIG-I KO animals displayed similar lung inflammation profiles as did WT mice, in terms of the protein concentration, total cell count, and inflammatory cell composition in the bronchoalveolar lavage fluid. RNA-Seq results demonstrated that all types of mice exhibited equivalent antiviral and inflammatory gene responses following IAV infection. Together, the results indicated that although RIG-I is important in innate cytokine responses in vitro, individual deletion of the genes encoding RIG-I or MAVS did not change survival or innate responses in vivo after IAV infection in mice.

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Influenza induces IL-8 and GM-CSF secretion by human alveolar epithelial cells through HGF/c-Met and TGF-α/EGFR signaling

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00290.2014 ◽

2015 ◽

Vol 308 (11) ◽

pp. L1178-L1188 ◽

Cited By ~ 35

Author(s):

Yoko Ito ◽

Kelly Correll ◽

Rachel L. Zemans ◽

Christina C. Leslie ◽

Robert C. Murphy ◽

...

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Immune Responses ◽

Influenza Infection ◽

Innate Immune ◽

Alveolar Epithelial Cells ◽

Innate Immune Responses ◽

Egfr Signaling ◽

Alveolar Epithelial ◽

Gm Csf

The most severe complication of influenza is viral pneumonia, which can lead to the acute respiratory distress syndrome. Alveolar epithelial cells (AECs) are the first cells that influenza virus encounters upon entering the alveolus. Infected epithelial cells produce cytokines that attract and activate neutrophils and macrophages, which in turn induce damage to the epithelial-endothelial barrier. Hepatocyte growth factor (HGF)/c-Met and transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGFR) are well known to regulate repair of damaged alveolar epithelium by stimulating cell migration and proliferation. Recently, TGF-α/EGFR signaling has also been shown to regulate innate immune responses in bronchial epithelial cells. However, little is known about whether HGF/c-Met signaling alters the innate immune responses and whether the innate immune responses in AECs are regulated by HGF/c-Met and TGF-α/EGFR. We hypothesized that HGF/c-Met and TGF-α/EGFR would regulate innate immune responses to influenza A virus infection in human AECs. We found that recombinant human HGF (rhHGF) and rhTGF-α stimulated primary human AECs to secrete IL-8 and granulocyte macrophage colony-stimulating factor (GM-CSF) strongly and IL-6 and monocyte chemotactic protein 1 moderately. Influenza infection stimulated the secretion of IL-8 and GM-CSF by AECs plated on rat-tail collagen through EGFR activation likely by TGF-α released from AECs and through c-Met activated by HGF secreted from lung fibroblasts. HGF secretion by fibroblasts was stimulated by AEC production of prostaglandin E2 during influenza infection. We conclude that HGF/c-Met and TGF-α/EGFR signaling enhances the innate immune responses by human AECs during influenza infections.

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