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Article ; Online: Experimental Model to Evaluate Resolution of Pneumonia.

Villabona-Rueda, Andres / Wang, Daniel / D'Alessio, Franco R

Journal of visualized experiments : JoVE

2023 , Issue 192

Abstract: Acute respiratory distress syndrome (ARDS) causes acute lung injury, characterized by rapid alveolar damage and severe hypoxemia. This, in turn, leads to high morbidity and mortality. Currently, there are no pre-clinical models that recapitulate the ... ...

Abstract	Acute respiratory distress syndrome (ARDS) causes acute lung injury, characterized by rapid alveolar damage and severe hypoxemia. This, in turn, leads to high morbidity and mortality. Currently, there are no pre-clinical models that recapitulate the complexity of human ARDS. However, infectious models of pneumonia (PNA) can replicate the main pathophysiological features of ARDS. Here, we describe a model of PNA induced by the intratracheal instillation of live Streptococcus pneumoniae and Klebsiella pneumoniae in C57BL6 mice. In order to evaluate and characterize the model, after inducing injury, we carried out serial measurements of body weight and bronchoalveolar lavage (BAL) for measuring markers of lung injury. Additionally, we harvested lungs for cell count and differentials, BAL protein quantification, cytospin, bacterial colony-forming unit counts, and histology. Lastly, high dimensional flow cytometry was performed. We propose this model as a tool to understand the immune landscape during the early and late resolution phases of lung injury.
MeSH term(s)	Animals ; Mice ; Humans ; Mice, Inbred C57BL ; Pneumonia ; Streptococcus pneumoniae ; Acute Lung Injury ; Dimercaprol ; Models, Theoretical
Chemical Substances	Dimercaprol (0CPP32S55X)
Language	English
Publishing date	2023-02-17
Publishing country	United States
Document type	Journal Article ; Video-Audio Media ; Research Support, N.I.H., Extramural
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/63925
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Article ; Online: Identification of specific causes of myelopathy in a large cohort of patients initially diagnosed with transverse myelitis.

Murphy, Olwen C / Barreras, Paula / Villabona-Rueda, Andres / Mealy, Maureen / Pardo, Carlos A

Journal of the neurological sciences

2022 Volume 442, Page(s) 120425

Abstract: Background and objectives: Identifying the etiologic diagnosis in patients presenting with myelopathy is essential in order to guide appropriate treatment and follow-up. We set out to examine the etiologic diagnosis after comprehensive clinical ... ...

Abstract	Background and objectives: Identifying the etiologic diagnosis in patients presenting with myelopathy is essential in order to guide appropriate treatment and follow-up. We set out to examine the etiologic diagnosis after comprehensive clinical evaluation and diagnostic work-up in a large cohort of patients referred to our specialized myelopathy clinic, and to explore the demographic profiles and symptomatic evolution of specific etiologic diagnoses. Methods: In this retrospective study of patients referred to the Johns Hopkins Myelitis and Myelopathy Center between 2006 and 2021 for evaluation of "transverse myelitis", the final etiologic diagnosis determined after comprehensive evaluation in each patient was reviewed and validated. Demographic characteristics and temporal profile of symptom evolution were recorded. Results: Of 1193 included patients, 772 (65%) were determined to have an inflammatory myelopathy and 421 (35%) were determined to have a non-inflammatory myelopathy. Multiple sclerosis/clinically isolated syndrome (n = 221, 29%) and idiopathic myelitis (n = 149, 19%) were the most frequent inflammatory diagnoses, while spinal cord infarction (n = 197, 47%) and structural causes of myelopathy (n = 108, 26%) were the most frequent non-inflammatory diagnoses. Compared to patients with inflammatory myelopathies, patients with non-inflammatory myelopathies were more likely to be older, male and experience chronic symptom evolution (p < 0.001 for all). Hyperacute symptom evolution was most frequent in patients with spinal cord infarction (74%), while chronic symptom evolution was most frequent in patients with structural causes of myelopathy (81%), arteriovenous fistula or arteriovenous malformation (81%), myelopathy associated with rheumatologic disorder (71%), and sarcoidosis-associated myelopathy (61%). Conclusions: Patients initially diagnosed with "transverse myelitis" are eventually found to have a more specific inflammatory or even non-inflammatory cause, potentially resulting in inappropriate treatment and follow-up. Demographic characteristics and temporal profile of symptom evolution may help inform a differential diagnosis in these patients. Etiological diagnosis of myelopathies would provide better therapeutic decisions.
MeSH term(s)	Humans ; Male ; Retrospective Studies ; Spinal Cord/diagnostic imaging ; Myelitis, Transverse/etiology ; Myelitis, Transverse/complications ; Spinal Cord Diseases/diagnosis ; Spinal Cord Diseases/etiology ; Myelitis/etiology ; Myelitis/complications ; Diagnosis, Differential ; Infarction/complications ; Magnetic Resonance Imaging
Language	English
Publishing date	2022-09-29
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80160-4
ISSN	1878-5883 ; 0022-510X ; 0374-8642
ISSN (online)	1878-5883
ISSN	0022-510X ; 0374-8642
DOI	10.1016/j.jns.2022.120425
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Article: The Evolving Concept of the Blood Brain Barrier (BBB): From a Single Static Barrier to a Heterogeneous and Dynamic Relay Center.

Villabona-Rueda, Andres / Erice, Clara / Pardo, Carlos A / Stins, Monique F

Frontiers in cellular neuroscience

2019 Volume 13, Page(s) 405

Abstract: The blood-brain barrier (BBB) helps maintain a tightly regulated microenvironment for optimal central nervous system (CNS) homeostasis and facilitates communications with the peripheral circulation. The brain endothelial cells, lining the brain's ... ...

Abstract	The blood-brain barrier (BBB) helps maintain a tightly regulated microenvironment for optimal central nervous system (CNS) homeostasis and facilitates communications with the peripheral circulation. The brain endothelial cells, lining the brain's vasculature, maintain close interactions with surrounding brain cells, e.g., astrocytes, pericytes and perivascular macrophages. This function facilitates critical intercellular crosstalk, giving rise to the concept of the neurovascular unit (NVU). The steady and appropriate communication between all components of the NVU is essential for normal CNS homeostasis and function, and dysregulation of one of its constituents can result in disease. Among the different brain regions, and along the vascular tree, the cellular composition of the NVU varies. Therefore, differential cues from the immediate vascular environment can affect BBB phenotype. To support the fluctuating metabolic and functional needs of the underlying neuropil, a specialized vascular heterogeneity is required. This is achieved by variances in barrier function, expression of transporters, receptors, and adhesion molecules. This mini-review will take you on a journey through evolving concepts surrounding the BBB, the NVU and beyond. Exploring classical experiments leading to new approaches will allow us to understand that the BBB is not merely a static separation between the brain and periphery but a closely regulated and interactive entity. We will discuss shifting paradigms, and ultimately aim to address the importance of BBB endothelial heterogeneity with regard to the function of the BBB within the NVU, and touch on its implications for different neuropathologies.
Language	English
Publishing date	2019-09-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2019.00405
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Article ; Online: Pathophysiology and neurologic sequelae of cerebral malaria.

Schiess, Nicoline / Villabona-Rueda, Andres / Cottier, Karissa E / Huether, Katherine / Chipeta, James / Stins, Monique F

Malaria journal

2020 Volume 19, Issue 1, Page(s) 266

Abstract: Cerebral malaria (CM), results from Plasmodium falciparum infection, and has a high mortality rate. CM survivors can retain life-long post CM sequelae, including seizures and neurocognitive deficits profoundly affecting their quality of life. As the ... ...

Abstract	Cerebral malaria (CM), results from Plasmodium falciparum infection, and has a high mortality rate. CM survivors can retain life-long post CM sequelae, including seizures and neurocognitive deficits profoundly affecting their quality of life. As the Plasmodium parasite does not enter the brain, but resides inside erythrocytes and are confined to the lumen of the brain's vasculature, the neuropathogenesis leading to these neurologic sequelae is unclear and under-investigated. Interestingly, postmortem CM pathology differs in brain regions, such as the appearance of haemorragic punctae in white versus gray matter. Various host and parasite factors contribute to the risk of CM, including exposure at a young age, parasite- and host-related genetics, parasite sequestration and the extent of host inflammatory responses. Thus far, several proposed adjunctive treatments have not been successful in the treatment of CM but are highly needed. The region-specific CM neuro-pathogenesis leading to neurologic sequelae is intriguing, but not sufficiently addressed in research. More attention to this may lead to the development of effective adjunctive treatments to address CM neurologic sequelae.
MeSH term(s)	Erythrocytes/parasitology ; Humans ; Malaria, Cerebral/complications ; Malaria, Cerebral/physiopathology ; Malaria, Falciparum/complications ; Malaria, Falciparum/physiopathology ; Plasmodium falciparum/physiology ; Quality of Life
Language	English
Publishing date	2020-07-23
Publishing country	England
Document type	Journal Article ; Review
ISSN	1475-2875
ISSN (online)	1475-2875
DOI	10.1186/s12936-020-03336-z
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Article: Airway and Systemic Prostaglandin E2 Association with COPD Symptoms and Macrophage Phenotype.

Tejwani, Vickram / Villabona-Rueda, Andres F / Khare, Pratik / Zhang, Cissy / Le, Anne / Putcha, Nirupama / D'Alessio, Franco / Alexis, Neil E / Hansel, Nadia N / Fawzy, Ashraf

Chronic obstructive pulmonary diseases (Miami, Fla.)

2023 Volume 10, Issue 2, Page(s) 159–169

Abstract: Background: Polymorphisms and products of the cyclooxygenase (COX) pathway have been associated with the development of chronic obstructive pulmonary disease (COPD) and adverse outcomes. COX-produced prostaglandin E2 (PGE-2) may play a role in the ... ...

Abstract	Background: Polymorphisms and products of the cyclooxygenase (COX) pathway have been associated with the development of chronic obstructive pulmonary disease (COPD) and adverse outcomes. COX-produced prostaglandin E2 (PGE-2) may play a role in the inflammation observed in COPD, potentially through deleterious airway macrophage polarization. A better understanding of the role of PGE-2 in COPD morbidity may inform trials for therapeutics targeting the COX pathway or PGE-2. Methods: Urine and induced sputum were collected from former smokers with moderate-severe COPD. The major urinary metabolite of PGE-2 (PGE-M) was measured, and ELISA was performed on sputum supernatant for PGE-2 airway measurement. Airway macrophages underwent flow cytometry phenotyping (surface CD64, CD80, CD163, CD206, and intracellular IL-1β, TGF-β1). Health information was obtained the same day as the biologic sample collection. Exacerbations were collected at baseline and then monthly telephone calls. Results: Among 30 former smokers with COPD (mean±SD age 66.4±8.88 years and forced expiratory volume in 1 second [FEV Conclusions: Elevated levels of sputum PGE-2, rather than systemic PGE-2, is associated with increased respiratory symptoms and history of exacerbation among individuals with COPD. Additional studies focused on mechanism of action are warranted.
Language	English
Publishing date	2023-03-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2771715-X
ISSN	2372-952X
ISSN	2372-952X
DOI	10.15326/jcopdf.2022.0375
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Article ; Online: Pseudomonas-dominant microbiome elicits sustained IL-1β upregulation in alveolar macrophages from lung transplant recipients.

Britton, Noel / Villabona-Rueda, Andres / Whiteside, Samantha A / Mathew, Joby / Kelley, Matthew / Agbor-Enoh, Sean / McDyer, John F / Christie, Jason D / Collman, Ronald G / Cox, Andrea L / Shah, Pali / D'Alessio, Franco

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation

2023 Volume 42, Issue 9, Page(s) 1166–1174

Abstract: Background: Isolation of Pseudomonas aeruginosa (PsA) is associated with increased BAL (bronchoalveolar lavage) inflammation and lung allograft injury in lung transplant recipients (LTR). However, the effect of PsA on macrophage responses in this ... ...

Abstract	Background: Isolation of Pseudomonas aeruginosa (PsA) is associated with increased BAL (bronchoalveolar lavage) inflammation and lung allograft injury in lung transplant recipients (LTR). However, the effect of PsA on macrophage responses in this population is incompletely understood. We examined human alveolar macrophage (AMΦ) responses to PsA and Pseudomonas dominant microbiome in healthy LTR. Methods: We stimulated THP-1 derived macrophages (THP-1MΦ) and human AMΦ from LTR with different bacteria and LTR BAL derived microbiome characterized as Pseudomonas-dominant. Macrophage responses were assessed by high dimensional flow cytometry, including their intracellular production of cytokines (TNF-α, IL-6, IL-8, IL-1β, IL-10, IL-1RA, and TGF-β). Pharmacological inhibitors were utilized to evaluate the role of the inflammasome in PsA-macrophage interaction. Results: We observed upregulation of pro-inflammatory cytokines (TNF-α, IL-6, IL-8, IL-1β) following stimulation by PsA compared to other bacteria (Staphylococcus aureus (S.Aur), Prevotella melaninogenica, Streptococcus pneumoniae) in both THP-1MΦ and LTR AMΦ, predominated by IL-1β. IL-1β production from THP-1MΦ was sustained after PsA stimulation for up to 96 hours and 48 hours in LTR AMΦ. Treatment with the inflammasome inhibitor BAY11-7082 abrogated THP-1MΦ IL-1β production after PsA exposure. BAL Pseudomonas-dominant microbiota elicited an increased IL-1β, similar to PsA, an effect abrogated by the addition of antibiotics. Conclusion: PsA and PsA-dominant lung microbiota induce sustained IL-1β production in LTR AMΦ. Pharmacological targeting of the inflammasome reduces PsA-macrophage-IL-1β responses, underscoring their use in lung transplant recipients.
MeSH term(s)	Humans ; Macrophages, Alveolar/metabolism ; Tumor Necrosis Factor-alpha ; Interleukin-6 ; Interleukin-8/metabolism ; Up-Regulation ; Pseudomonas/metabolism ; Inflammasomes ; Transplant Recipients ; Arthritis, Psoriatic ; Lung/metabolism ; Cytokines/metabolism
Chemical Substances	Tumor Necrosis Factor-alpha ; Interleukin-6 ; Interleukin-8 ; Inflammasomes ; Cytokines
Language	English
Publishing date	2023-04-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1062522-7
ISSN	1557-3117 ; 1053-2498
ISSN (online)	1557-3117
ISSN	1053-2498
DOI	10.1016/j.healun.2023.04.005
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Article ; Online: Sulforaphane exhibits antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses in vitro and in mice.

Ordonez, Alvaro A / Bullen, C Korin / Villabona-Rueda, Andres F / Thompson, Elizabeth A / Turner, Mitchell L / Merino, Vanessa F / Yan, Yu / Kim, John / Davis, Stephanie L / Komm, Oliver / Powell, Jonathan D / D'Alessio, Franco R / Yolken, Robert H / Jain, Sanjay K / Jones-Brando, Lorraine

Communications biology

2022 Volume 5, Issue 1, Page(s) 242

Abstract: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has incited a global health crisis. Currently, there are limited therapeutic options for the prevention and treatment of SARS-CoV-2 infections. ...

Abstract	Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has incited a global health crisis. Currently, there are limited therapeutic options for the prevention and treatment of SARS-CoV-2 infections. We evaluated the antiviral activity of sulforaphane (SFN), the principal biologically active phytochemical derived from glucoraphanin, the naturally occurring precursor present in high concentrations in cruciferous vegetables. SFN inhibited in vitro replication of six strains of SARS-CoV-2, including Delta and Omicron, as well as that of the seasonal coronavirus HCoV-OC43. Further, SFN and remdesivir interacted synergistically to inhibit coronavirus infection in vitro. Prophylactic administration of SFN to K18-hACE2 mice prior to intranasal SARS-CoV-2 infection significantly decreased the viral load in the lungs and upper respiratory tract and reduced lung injury and pulmonary pathology compared to untreated infected mice. SFN treatment diminished immune cell activation in the lungs, including significantly lower recruitment of myeloid cells and a reduction in T cell activation and cytokine production. Our results suggest that SFN should be explored as a potential agent for the prevention or treatment of coronavirus infections.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/therapeutic use ; Alanine/analogs & derivatives ; Alanine/therapeutic use ; Animals ; Antiviral Agents/therapeutic use ; Caco-2 Cells ; Chlorocebus aethiops ; Common Cold/drug therapy ; Common Cold/virology ; Coronavirus Infections/drug therapy ; Coronavirus Infections/immunology ; Coronavirus Infections/virology ; Coronavirus OC43, Human ; Cytokines/immunology ; Drug Synergism ; Humans ; Isothiocyanates/therapeutic use ; Lung/immunology ; Lung/virology ; Macrophages, Alveolar/immunology ; Male ; Mice, Transgenic ; SARS-CoV-2 ; Spleen/immunology ; Sulfoxides/therapeutic use ; T-Lymphocytes/immunology ; Vero Cells ; Viral Load ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Cytokines ; Isothiocyanates ; Sulfoxides ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; sulforaphane (GA49J4310U) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2022-03-18
Publishing country	England
Document type	Journal Article
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-03189-z
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Article: Sulforaphane exhibits in vitro and in vivo antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses.

Ordonez, Alvaro A / Bullen, C Korin / Villabona-Rueda, Andres F / Thompson, Elizabeth A / Turner, Mitchell L / Davis, Stephanie L / Komm, Oliver / Powell, Jonathan D / D'Alessio, Franco R / Yolken, Robert H / Jain, Sanjay K / Jones-Brando, Lorraine

bioRxiv : the preprint server for biology

2021

Abstract: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has incited a global health crisis. Currently, there are no orally available medications for prophylaxis for those exposed to SARS-CoV-2 and ... ...

Abstract	Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has incited a global health crisis. Currently, there are no orally available medications for prophylaxis for those exposed to SARS-CoV-2 and limited therapeutic options for those who develop COVID-19. We evaluated the antiviral activity of sulforaphane (SFN), a naturally occurring, orally available, well-tolerated, nutritional supplement present in high concentrations in cruciferous vegetables with limited side effects. SFN inhibited in vitro replication of four strains of SARS-CoV-2 as well as that of the seasonal coronavirus HCoV-OC43. Further, SFN and remdesivir interacted synergistically to inhibit coronavirus infection in vitro. Prophylactic administration of SFN to K18-hACE2 mice prior to intranasal SARS-CoV-2 infection significantly decreased the viral load in the lungs and upper respiratory tract and reduced lung injury and pulmonary pathology compared to untreated infected mice. SFN treatment diminished immune cell activation in the lungs, including significantly lower recruitment of myeloid cells and a reduction in T cell activation and cytokine production. Our results suggest that SFN is a promising treatment for prevention of coronavirus infection or treatment of early disease.
Language	English
Publishing date	2021-03-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.03.25.437060
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Article ; Online: Sulforaphane exhibits in vitro and in vivo antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses

Ordonez, Alvaro A / Bullen, Cynthia K / Villabona-Rueda, Andres F / Thompson, Elizabeth A / Turner, Mitchell L / Davis, Stephanie L / Komm, Oliver / Powell, Jonathan D / D'Alessio, Franco R / Yolken, Robert H / Jain, Sanjay K / Jones-Brando, Lorraine

bioRxiv

Abstract: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has incited a global health crisis. Currently, there are no orally available medications for prophylaxis for those exposed to SARS-CoV-2 and ... ...

Abstract	Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has incited a global health crisis. Currently, there are no orally available medications for prophylaxis for those exposed to SARS-CoV-2 and limited therapeutic options for those who develop COVID-19. We evaluated the antiviral activity of sulforaphane (SFN), a naturally occurring, orally available, well-tolerated, nutritional supplement present in high concentrations in cruciferous vegetables with limited side effects. SFN inhibited in vitro replication of four strains of SARS-CoV-2 as well as that of the seasonal coronavirus HCoV-OC43. Further, SFN and remdesivir interacted synergistically to inhibit coronavirus infection in vitro. Prophylactic administration of SFN to K18-hACE2 mice prior to intranasal SARS-CoV-2 infection significantly decreased the viral load in the lungs and upper respiratory tract and reduced lung injury and pulmonary pathology compared to untreated infected mice. SFN treatment diminished immune cell activation in the lungs, including significantly lower recruitment of myeloid cells and a reduction in T cell activation and cytokine production. Our results suggest that SFN is a promising treatment for prevention of coronavirus infection or treatment of early disease.
Keywords	covid19
Language	English
Publishing date	2021-03-25
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.03.25.437060
Database	COVID19

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