The use of plethysmography in determining the severity of lung pathology in a mouse model of minimally lethal influenza virus infection

Julander, Justin G.; Kesler, Kyle; Wettere, Arnaud J. Van; Morrey, John D.; Smee, Donald F.

doi:10.1016/j.antiviral.2014.05.002

Cited by 13 publications

(13 citation statements)

References 8 publications

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“…P ENH is an empirical measure calculated by

, where PEF is the peak expiratory flow, PIF is the peak inspiratory flow, T e represents the time of expiration, and T r represents the relaxation time to 36% of the peak expiration pressure ( 62 ). P ENH has been controversially linked to airway hyperresponsiveness, obstruction, and bronchoconstriction but has been used in several viral models of airway infection, where increases in the P ENH value correlate with increased lung pathology following respiratory viral infection ( 40 , 42 , 62 – 64 ). EF 50 indicates the flow rate at 50% of the tidal volume.…”

Section: Methodsmentioning

confidence: 99%

Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection

Totura

Whitmore

Agnihothram

et al. 2015

mBio

423

465

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Toll-like receptors (TLRs) are sensors that recognize molecular patterns from viruses, bacteria, and fungi to initiate innate immune responses to invading pathogens. The emergence of highly pathogenic coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) is a concern for global public health, as there is a lack of efficacious vaccine platforms and antiviral therapeutic strategies. Previously, it was shown that MyD88, an adaptor protein necessary for signaling by multiple TLRs, is a required component of the innate immune response to mouse-adapted SARS-CoV infection in vivo. Here, we demonstrate that TLR3−/−, TLR4−/−, and TRAM−/− mice are more susceptible to SARS-CoV than wild-type mice but experience only transient weight loss with no mortality in response to infection. In contrast, mice deficient in the TLR3/TLR4 adaptor TRIF are highly susceptible to SARS-CoV infection, showing increased weight loss, mortality, reduced lung function, increased lung pathology, and higher viral titers. Distinct alterations in inflammation were present in TRIF−/− mice infected with SARS-CoV, including excess infiltration of neutrophils and inflammatory cell types that correlate with increased pathology of other known causes of acute respiratory distress syndrome (ARDS), including influenza virus infections. Aberrant proinflammatory cytokine, chemokine, and interferon-stimulated gene (ISG) signaling programs were also noted following infection of TRIF−/− mice that were similar to those seen in human patients with poor disease outcome following SARS-CoV or MERS-CoV infection. These findings highlight the importance of TLR adaptor signaling in generating a balanced protective innate immune response to highly pathogenic coronavirus infections.

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“…P ENH is an empirical measure calculated by

Section: Methodsmentioning

confidence: 99%

Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection

Totura

Whitmore

Agnihothram

et al. 2015

mBio

423

465

View full text Add to dashboard Cite

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“…Enhanced pause (Penh) was used as a pulmonary function test as it represents a good measure of airway resistance. In the context of whole body, restrained, flow plethysmography (as was used here), Penh has been shown to be an adequate quantitative measure of resistance, particularly when pathology is utilized to corroborate measurements(32, 33). …”

Section: Methodsmentioning

confidence: 99%

Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain-death induced immunological injury post–lung transplant

Cheng

Patel

Lei

et al. 2018

American Journal of Transplantation

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Donor brain death (BD) is an inherent part of lung transplantation (LTx) and a key contributor to ischemia-reperfusion injury (IRI). Complement activation occurs as a consequence of BD in other solid organ Tx and exacerbates IRI, but the role of complement in LTx has not been investigated. Here, we investigate the utility of delivering nebulized C3a receptor antagonist (C3aRA) pretransplant to BD donor lungs in order to reduce post-LTx IRI. BD was induced in Balb/c donors, and lungs nebulized with C3aRA or vehicle 30 minutes prior to lung procurement. Lungs were then cold stored for 18 hours before transplantation into C57Bl/6 recipients. Donor lungs from living donors (LD) were removed and similarly stored. At 6 hours and 5 days post-LTx, recipients of BD donor lungs had exacerbated IRI and acute rejection (AR), respectively, compared to recipients receiving LD lungs, as determined by increased histopathological injury, immune cells, and cytokine levels. A single pretransplant nebulized dose of C3aRA to the donor significantly reduced IRI as compared to vehicle-treated BD donors, and returned IRI and AR grades to that seen following LD LTx. These data demonstrate a role for complement inhibition in the amelioration of IRI post-LTx in the context of donor BD.

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“…Recently, unrestrained whole body lung plethysmography has been shown to be able to monitor progressive pneumonia robustly utilizing tidal volume, breathing frequencies, and enhanced pause (Penh) as measures of lung function ( Figure 2E) (90,91). While tidal volume and breathing frequencies are being commonly utilized, Penh can only be used in unrestrained plethysmography if the gas in the plethysmograph is pre-conditioned to body temperature and humidity, however, this lung function parameter as a measurement for airway restriction is much debated (92,93).…”

Section: Disease Endpoints For Translational Studiesmentioning

confidence: 99%

Animal models of hospital-acquired pneumonia: current practices and future perspectives

Bielen¹,

Jongers²,

Malhotra-Kumar³

et al. 2017

Ann. Transl. Med.

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Lower respiratory tract infections are amongst the leading causes of mortality and morbidity worldwide. Especially in hospital settings and more particularly in critically ill ventilated patients, nosocomial pneumonia is one of the most serious infectious complications frequently caused by opportunistic pathogens.Pseudomonas aeruginosa is one of the most important causes of ventilator-associated pneumonia as well as the major cause of chronic pneumonia in cystic fibrosis patients. Animal models of pneumonia allow us to investigate distinct types of pneumonia at various disease stages, studies that are not possible in patients.Different animal models of pneumonia such as one-hit acute pneumonia models, ventilator-associated pneumonia models and biofilm pneumonia models associated with cystic fibrosis have been extensively studied and have considerably aided our understanding of disease pathogenesis and testing and developing new treatment strategies. The present review aims to guide investigators in choosing appropriate animal pneumonia models by describing and comparing the relevant characteristics of each model using P. aeruginosa as a model etiology for hospital-acquired pneumonia. Key to establishing and studying these animal models of infection are well-defined end-points that allow precise monitoring and characterization of disease development that could ultimately aid in translating these findings to patient populations in order to guide therapy. In this respect, and discussed here, is the development of humanized animal models of bacterial pneumonia that could offer unique advantages to study bacterial virulence factor expression and host cytokine production for translational purposes.

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The use of plethysmography in determining the severity of lung pathology in a mouse model of minimally lethal influenza virus infection

Cited by 13 publications

References 8 publications

Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection

Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection

Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain-death induced immunological injury post–lung transplant

Animal models of hospital-acquired pneumonia: current practices and future perspectives

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