Postinfection A77-1726 Treatment Improves Cardiopulmonary Function in H1N1 Influenza-Infected Mice

Aeffner, Famke; Bratasz, Anna; Flaño, Emilio; Powell, Kimerly; Davis, Ian C.

doi:10.1165/rcmb.2012-0112oc

Cited by 22 publications

(44 citation statements)

References 54 publications

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“…Influenza A virus infection induced an adenosine response in the lung. Previously, we showed that BALF ATP content is increased in influenza A WSN/33 (H1N1) virus-infected mice (6,7). Using specific inhibitors, we also showed that bronchoalveolar epithelial A 1 -AdoRs are activated following infection (6).…”

Section: Resultsmentioning

confidence: 86%

“…Conscious mice were weighed every other day following infection, and carotid arterial O 2 saturation was recorded by pulse oximetry, as in our previous studies (7,24). Data for each experimental group were derived from at least three independent infections.…”

Section: Methodsmentioning

confidence: 99%

“…Controls received an equal volume of the vehicle. Preparation of tissues for histopathologic evaluation and measurement of viral titers were performed as previously described (6,7).…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, weight loss was reduced in WT-to-A 1 -KO BMT mice and DP-CPX-treated WT mice, although the reason for these effects is unclear. However, we believe that these commonly used outcome measures for influenza studies in the mouse model provide little information regarding the severity of influenza-induced lung dysfunction and ALI, which is the focus of our studies (7,28). Even in the most severe cases, influenza virus-infected human subjects do not experience the extremely rapid, severe, and probably intrinsically lethal weight loss observed in influenza virus-infected mice (Ն30% in 6 days).…”

Section: Fig 7 Lung Compliance and Airway Resistance Were Not Alteredmentioning

confidence: 99%

“…We have previously shown that influenza A virus infection resulted in an increase in BALF ATP levels in mice (Mus musculus) (6). This effect was reversed by treatment with the de novo pyrimidine synthesis inhibitor A77-1726, indicating that released ATP was derived from increased de novo nucleotide synthesis in response to infection (7).…”

mentioning

confidence: 98%

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Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Aeffner

Woods

Davis

2014

J Virol

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We have shown that bronchoalveolar epithelial A 1 -adenosine receptors (A 1 -AdoR) are activated in influenza A virus-infected mice. Alveolar macrophages and neutrophils also express A 1 -AdoRs, and we hypothesized that activation of A 1 -AdoRs on these cells will promote macrophage and neutrophil chemotaxis and activation and thereby play a role in the pathogenesis of influenza virus-induced acute lung injury. Wild-type (WT) C57BL/6 mice, congenic A 1 -AdoR knockout (A 1 -KO) mice, and mice that had undergone reciprocal bone marrow transfer were inoculated intranasally with 10,000 PFU/mouse influenza A/WSN/33 (H1N1) virus. Alternatively, WT mice underwent daily treatment with the A 1 -AdoR antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) from 1 day prior to inoculation. Infection increased bronchoalveolar lining fluid (BALF) adenosine comparably in WT and A 1 -KO mice. Infection of WT mice resulted in reduced carotid arterial O 2 saturation (hypoxemia), lung pathology, pulmonary edema, reduced lung compliance, increased basal airway resistance, and hyperresponsiveness to methacholine. These effects were absent or significantly attenuated in A 1 -KO mice. Levels of BALF leukocytes, gamma interferon (IFN-␥), and interleukin 10 (IL-10) were significantly reduced in infected A 1 -KO mice, but levels of KC, IP-10, and MCP-1 were increased. Reciprocal bone marrow transfer resulted in WT-like lung injury severity, but BALF leukocyte levels increased only in WT and A 1 -KO mice with WT bone barrow. Hypoxemia, pulmonary edema, and levels of BALF alveolar macrophages, neutrophils, IFN-␥, and IL-10 were reduced in DPCPX-treated WT mice. Levels of viral replication did not differ between mouse strains or treatment groups. These findings indicate that adenosine activation of leukocyte A 1 -AdoRs plays a significant role in their recruitment to the infected lung and contributes to influenza pathogenesis. A 1 -AdoR inhibitor therapy may therefore be beneficial in patients with influenza virus-induced lung injury. IMPORTANCEBecause antiviral drugs are of limited efficacy in patients hospitalized for influenza virus-induced respiratory failure, there is an urgent need for new therapeutics that can limit the progression of lung injury and reduce influenza death rates. We show that influenza A virus infection results in increased production of the nucleoside adenosine in the mouse lung and that activation of A 1 -subtype adenosine receptors by adenosine contributes significantly to both recruitment of innate immune cells to the lung and development of acute lung injury following influenza virus infection. We also show that treatment with an A 1 -adenosine receptor antagonist reduces the severity of lung injury in influenza virus-infected mice. Our findings indicate that adenosine plays an important and previously unrecognized role in the innate immune response to influenza virus infection and suggest that drugs which can inhibit either generation of adenosine or activation of A 1 -adenosine receptors may be beneficia...

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Section: Resultsmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

“…Controls received an equal volume of the vehicle. Preparation of tissues for histopathologic evaluation and measurement of viral titers were performed as previously described (6,7).…”

Section: Methodsmentioning

confidence: 99%

Section: Fig 7 Lung Compliance and Airway Resistance Were Not Alteredmentioning

confidence: 99%

mentioning

confidence: 98%

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Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Aeffner

Woods

Davis

2014

J Virol

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Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury

Hasan

Blankman

Nieman

2017

Purinergic Signalling

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Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis.Electronic supplementary materialThe online version of this article (doi:10.1007/s11302-017-9564-5) contains supplementary material, which is available to authorized users.

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DNA repair and genomic stability in lungs affected by acute injury

Sergio

Mencalha

Fonseca

et al. 2019

Biomedicine & Pharmacotherapy

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Postinfection A77-1726 Treatment Improves Cardiopulmonary Function in H1N1 Influenza-Infected Mice

Cited by 22 publications

References 54 publications

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury

DNA repair and genomic stability in lungs affected by acute injury

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Postinfection A77-1726 Treatment Improves Cardiopulmonary Function in H1N1 Influenza-Infected Mice

Cited by 22 publications

References 54 publications

Activation of A 1 -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Activation of A 1 -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury

DNA repair and genomic stability in lungs affected by acute injury

Contact Info

Product

Resources

About

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus