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  1. Article ; Online: A Murine Model of Vesicant-Induced Acute Lung Injury.

    Zafar, Iram / Manzoor, Shajer / Mariappan, Nithya / Ahmad, Shama / Athar, Mohammad / Antony, Veena / Ahmad, Aftab

    The Journal of pharmacology and experimental therapeutics

    2024  Volume 388, Issue 2, Page(s) 568–575

    Abstract: Burn injuries including those caused by chemicals can result in systemic effects and acute lung injury (ALI). Cutaneous exposure to Lewisite, a warfare and chemical burn agent, also causes ALI. To overcome the limitations in conducting direct research on ...

    Abstract Burn injuries including those caused by chemicals can result in systemic effects and acute lung injury (ALI). Cutaneous exposure to Lewisite, a warfare and chemical burn agent, also causes ALI. To overcome the limitations in conducting direct research on Lewisite-induced ALI in a laboratory setting, an animal model was developed using phenylarsine oxide (PAO) as a surrogate for Lewisite. Due to lack of a reliable animal model mimicking the effects of such exposures, development of effective therapies to treat such injuries is challenging. We demonstrated that a single cutaneous exposure to PAO resulted in disruption of the alveolar-capillary barrier as evidenced by elevated protein levels in the bronchoalveolar lavage fluid (BALF). BALF supernatant of PAO-exposed animals had increased levels of high mobility group box 1, a damage associated molecular pattern molecule. Arterial blood-gas measurements showed decreased pH, increased PaCO
    MeSH term(s) Mice ; Animals ; Irritants/adverse effects ; Disease Models, Animal ; Vascular Endothelial Growth Factor A/metabolism ; Lung/metabolism ; Acute Lung Injury/chemically induced ; Acute Lung Injury/metabolism ; Bronchoalveolar Lavage Fluid/chemistry ; Interleukin-6/metabolism ; Arsenicals
    Chemical Substances lewisite (0N54LGU5WS) ; Irritants ; Vascular Endothelial Growth Factor A ; oxophenylarsine (0HUR2WY345) ; Interleukin-6 ; Arsenicals
    Language English
    Publishing date 2024-01-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3106-9
    ISSN 1521-0103 ; 0022-3565
    ISSN (online) 1521-0103
    ISSN 0022-3565
    DOI 10.1124/jpet.123.001780
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  2. Article ; Online: Epigenetic underpinnings of inflammation: Connecting the dots between pulmonary diseases, lung cancer and COVID-19.

    Ahmad, Shama / Manzoor, Shajer / Siddiqui, Simmone / Mariappan, Nithya / Zafar, Iram / Ahmad, Aamir / Ahmad, Aftab

    Seminars in cancer biology

    2021  Volume 83, Page(s) 384–398

    Abstract: Inflammation is an essential component of several respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and acute respiratory distress syndrome (ARDS). It is central to lung cancer, the leading cancer in terms of associated ... ...

    Abstract Inflammation is an essential component of several respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and acute respiratory distress syndrome (ARDS). It is central to lung cancer, the leading cancer in terms of associated mortality that has affected millions of individuals worldwide. Inflammation and pulmonary manifestations are also the major causes of COVID-19 related deaths. Acute hyperinflammation plays an important role in the COVID-19 disease progression and severity, and development of protective immunity against the virus is greatly sought. Further, the severity of COVID-19 is greatly enhanced in lung cancer patients, probably due to the genes such as ACE2, TMPRSS2, PAI-1 and furin that are commonly involved in cancer progression as well as SAR-CoV-2 infection. The importance of inflammation in pulmonary manifestations, cancer and COVID-19 calls for a closer look at the underlying processes, particularly the associated increase in IL-6 and other cytokines, the dysregulation of immune cells and the coagulation pathway. Towards this end, several reports have identified epigenetic regulation of inflammation at different levels. Expression of several key inflammation-related cytokines, chemokines and other genes is affected by methylation and acetylation while non-coding RNAs, including microRNAs as well as long non-coding RNAs, also affect the overall inflammatory responses. Select miRNAs can regulate inflammation in COVID-19 infection, lung cancer as well as other inflammatory lung diseases, and can serve as epigenetic links that can be therapeutically targeted. Furthermore, epigenetic changes also mediate the environmental factors-induced inflammation. Therefore, a better understanding of epigenetic regulation of inflammation can potentially help develop novel strategies to prevent, diagnose and treat chronic pulmonary diseases, lung cancer and COVID-19.
    MeSH term(s) COVID-19/genetics ; Cytokines ; Epigenesis, Genetic ; Humans ; Inflammation/genetics ; Lung Diseases/genetics ; Lung Neoplasms/genetics ; MicroRNAs/genetics ; SARS-CoV-2
    Chemical Substances Cytokines ; MicroRNAs
    Language English
    Publishing date 2021-01-20
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 1033980-2
    ISSN 1096-3650 ; 1044-579X
    ISSN (online) 1096-3650
    ISSN 1044-579X
    DOI 10.1016/j.semcancer.2021.01.003
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  3. Article ; Online: Blueberry supplementation attenuates oxidative stress within monocytes and modulates immune cell levels in adults with metabolic syndrome: a randomized, double-blind, placebo-controlled trial.

    Nair, Anand R / Mariappan, Nithya / Stull, April J / Francis, Joseph

    Food & function

    2017  Volume 8, Issue 11, Page(s) 4118–4128

    Abstract: Background: Blueberries (BB) have been shown to improve insulin sensitivity and endothelial function in obese and pre-diabetic humans, and decrease oxidative stress and inflammation, and ameliorate cardio-renal damage in rodents. This indicates that ... ...

    Abstract Background: Blueberries (BB) have been shown to improve insulin sensitivity and endothelial function in obese and pre-diabetic humans, and decrease oxidative stress and inflammation, and ameliorate cardio-renal damage in rodents. This indicates that blueberries have a systemic effect and are not limited to a particular organ system. In order for blueberries to exert beneficial effects on the whole body, the mechanism would logically have to operate through modulation of cellular humoral factors.
    Objective: This study investigated the role of blueberries in modulating immune cell levels and attenuating circulatory and monocyte inflammation and oxidative stress in metabolic syndrome (MetS) subjects.
    Design: A double-blind, randomized and placebo-controlled study was conducted in adults with MetS, in which they received a blueberry (22.5 g freeze-dried) or placebo smoothie twice daily for six weeks. Free radical production in the whole blood and monocytes, dendritic cell (DC) levels, expression of cytokines in monocytes and serum inflammatory markers were assessed pre- and post-intervention.
    Results: Baseline free radical levels in MetS subjects' samples were not different between groups. Treatment with blueberries markedly decreased superoxide and total reactive oxygen species (ROS) in whole blood and monocytes compared to the placebo (p ≤ 0.05). The baseline DC numbers in MetS subjects' samples in both groups were not different, however treatment with blueberries significantly increased myeloid DC (p ≤ 0.05) and had no effect on plasmacytoid cells. Blueberry treatment decreased monocyte gene expression of TNFα, IL-6, TLR4 and reduced serum GMCSF in MetS subjects when compared to the placebo treatment (p ≤ 0.05).
    Conclusions: The findings of the current study demonstrate that blueberries exert immunomodulatory effects and attenuate oxidative stress and inflammation in adults with MetS.
    Language English
    Publishing date 2017-11-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 2612033-1
    ISSN 2042-650X ; 2042-6496
    ISSN (online) 2042-650X
    ISSN 2042-6496
    DOI 10.1039/c7fo00815e
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  4. Article ; Online: Pulmonary pathogenesis in a murine model of inhaled arsenical exposure.

    Mariappan, Nithya / Zafar, Iram / Robichaud, Annette / Wei, Chih-Chang / Shakil, Shazia / Ahmad, Aamir / Goymer, Hannah M / Abdelsalam, Ayat / Kashyap, Mahendra P / Foote, Jeremy B / Bae, Sejong / Agarwal, Anupam / Ahmad, Shama / Athar, Mohammad / Antony, Veena B / Ahmad, Aftab

    Archives of toxicology

    2023  Volume 97, Issue 7, Page(s) 1847–1858

    Abstract: Arsenic trioxide (ATO), an inorganic arsenical, is a toxic environmental contaminant. It is also a widely used chemical with industrial and medicinal uses. Significant public health risk exists from its intentional or accidental exposure. The pulmonary ... ...

    Abstract Arsenic trioxide (ATO), an inorganic arsenical, is a toxic environmental contaminant. It is also a widely used chemical with industrial and medicinal uses. Significant public health risk exists from its intentional or accidental exposure. The pulmonary pathology of acute high dose exposure is not well defined. We developed and characterized a murine model of a single inhaled exposure to ATO, which was evaluated 24 h post-exposure. ATO caused hypoxemia as demonstrated by arterial blood-gas measurements. ATO administration caused disruption of alveolar-capillary membrane as shown by increase in total protein and IgM in the bronchoalveolar lavage fluid (BALF) supernatant and an onset of pulmonary edema. BALF of ATO-exposed mice had increased HMGB1, a damage-associated molecular pattern (DAMP) molecule, and differential cell counts revealed increased neutrophils. BALF supernatant also showed an increase in protein levels of eotaxin/CCL-11 and MCP-3/CCL-7 and a reduction in IL-10, IL-19, IFN-γ, and IL-2. In the lung of ATO-exposed mice, increased protein levels of G-CSF, CXCL-5, and CCL-11 were noted. Increased mRNA levels of TNF-a, and CCL2 in ATO-challenged lungs further supported an inflammatory pathogenesis. Neutrophils were increased in the blood of ATO-exposed animals. Pulmonary function was also evaluated using flexiVent. Consistent with an acute lung injury phenotype, respiratory and lung elastance showed significant increase in ATO-exposed mice. PV loops showed a downward shift and a decrease in inspiratory capacity in the ATO mice. Flow-volume curves showed a decrease in FEV
    MeSH term(s) Humans ; Mice ; Animals ; Disease Models, Animal ; Lung/pathology ; Bronchoalveolar Lavage Fluid/chemistry ; Acute Lung Injury ; Arsenicals
    Chemical Substances Arsenicals
    Language English
    Publishing date 2023-05-11
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-023-03503-6
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  5. Article ; Online: Extracellular nucleic acid scavenging rescues rats from sulfur mustard analog-induced lung injury and mortality.

    Mariappan, Nithya / Husain, Maroof / Zafar, Iram / Singh, Vinodkumar / Smithson, Kenneth G / Crowe, David R / Pittet, Jean-Francois / Ahmad, Shama / Ahmad, Aftab

    Archives of toxicology

    2020  Volume 94, Issue 4, Page(s) 1321–1334

    Abstract: Sulfur mustard (SM) is a highly toxic war chemical that causes significant morbidity and mortality and lacks any effective therapy. Rats exposed to aerosolized CEES (2-chloroethyl ethyl sulfide; 10% in ethanol), an analog of SM, developed acute ... ...

    Abstract Sulfur mustard (SM) is a highly toxic war chemical that causes significant morbidity and mortality and lacks any effective therapy. Rats exposed to aerosolized CEES (2-chloroethyl ethyl sulfide; 10% in ethanol), an analog of SM, developed acute respiratory distress syndrome (ARDS), which is characterized by increased inflammation, hypoxemia and impaired gas exchange. We observed elevated levels of extracellular nucleic acids (eNA) in the bronchoalveolar lavage fluid (BALF) of CEES-exposed animals. eNA can induce inflammation, coagulation and barrier dysfunction. Treatment with hexadimethrine bromide (HDMBr; 10 mg/kg), an eNA neutralizing agent, 2 h post-exposure, reduced lung injury, inhibited disruption of alveolar-capillary barrier, improved blood oxygenation (PaO
    MeSH term(s) Animals ; Chemical Warfare Agents/toxicity ; Lung ; Lung Injury ; Male ; Mustard Gas/analogs & derivatives ; Mustard Gas/toxicity ; Nucleic Acids/metabolism ; Rats ; Toxicity Tests
    Chemical Substances Chemical Warfare Agents ; Nucleic Acids ; 2-chloroethyl ethyl sulfide (693-07-2) ; Mustard Gas (T8KEC9FH9P)
    Language English
    Publishing date 2020-03-10
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-020-02699-1
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  6. Article: Blueberry supplementation attenuates oxidative stress within monocytes and modulates immune cell levels in adults with metabolic syndrome: a randomized, double-blind, placebo-controlled trial

    Nair, Anand R / Mariappan, Nithya / Stull, April J / Francis, Joseph

    Food & function. 2017 Nov. 15, v. 8, no. 11

    2017  

    Abstract: Background: Blueberries (BB) have been shown to improve insulin sensitivity and endothelial function in obese and pre-diabetic humans, and decrease oxidative stress and inflammation, and ameliorate cardio-renal damage in rodents. This indicates that ... ...

    Abstract Background: Blueberries (BB) have been shown to improve insulin sensitivity and endothelial function in obese and pre-diabetic humans, and decrease oxidative stress and inflammation, and ameliorate cardio-renal damage in rodents. This indicates that blueberries have a systemic effect and are not limited to a particular organ system. In order for blueberries to exert beneficial effects on the whole body, the mechanism would logically have to operate through modulation of cellular humoral factors. Objective: This study investigated the role of blueberries in modulating immune cell levels and attenuating circulatory and monocyte inflammation and oxidative stress in metabolic syndrome (MetS) subjects. Design: A double-blind, randomized and placebo-controlled study was conducted in adults with MetS, in which they received a blueberry (22.5 g freeze-dried) or placebo smoothie twice daily for six weeks. Free radical production in the whole blood and monocytes, dendritic cell (DC) levels, expression of cytokines in monocytes and serum inflammatory markers were assessed pre- and post-intervention. Results: Baseline free radical levels in MetS subjects’ samples were not different between groups. Treatment with blueberries markedly decreased superoxide and total reactive oxygen species (ROS) in whole blood and monocytes compared to the placebo (p ≤ 0.05). The baseline DC numbers in MetS subjects’ samples in both groups were not different, however treatment with blueberries significantly increased myeloid DC (p ≤ 0.05) and had no effect on plasmacytoid cells. Blueberry treatment decreased monocyte gene expression of TNFα, IL-6, TLR4 and reduced serum GMCSF in MetS subjects when compared to the placebo treatment (p ≤ 0.05). Conclusions: The findings of the current study demonstrate that blueberries exert immunomodulatory effects and attenuate oxidative stress and inflammation in adults with MetS.
    Keywords Toll-like receptor 4 ; adults ; blood serum ; blueberries ; dendritic cells ; free radicals ; freeze drying ; humans ; immunomodulators ; inflammation ; insulin resistance ; interleukin-6 ; metabolic syndrome ; monocytes ; oxidative stress ; placebos ; reactive oxygen species ; rodents ; tumor necrosis factor-alpha
    Language English
    Dates of publication 2017-1115
    Size p. 4118-4128.
    Publishing place The Royal Society of Chemistry
    Document type Article
    ZDB-ID 2612033-1
    ISSN 2042-650X ; 2042-6496
    ISSN (online) 2042-650X
    ISSN 2042-6496
    DOI 10.1039/c7fo00815e
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  7. Article: Echocardiographic, Biochemical, and Electrocardiographic Correlates Associated With Progressive Pulmonary Arterial Hypertension.

    Zaky, Ahmed / Zafar, Iram / Masjoan-Juncos, Juan Xavier / Husain, Maroof / Mariappan, Nithya / Morgan, Charity J / Hamid, Tariq / Frölich, Michael A / Ahmad, Shama / Ahmad, Aftab

    Frontiers in cardiovascular medicine

    2021  Volume 8, Page(s) 705666

    Abstract: Background: ...

    Abstract Background:
    Language English
    Publishing date 2021-07-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2781496-8
    ISSN 2297-055X
    ISSN 2297-055X
    DOI 10.3389/fcvm.2021.705666
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  8. Article ; Online: Behavioral and Neuronal Effects of Inhaled Bromine Gas: Oxidative Brain Stem Damage.

    Shakil, Shazia / Masjoan Juncos, Juan Xavier / Mariappan, Nithya / Zafar, Iram / Amudhan, Apoorva / Amudhan, Archita / Aishah, Duha / Siddiqui, Simmone / Manzoor, Shajer / Santana, Cristina M / Rumbeiha, Wilson K / Salim, Samina / Ahmad, Aftab / Ahmad, Shama

    International journal of molecular sciences

    2021  Volume 22, Issue 12

    Abstract: The risk of accidental bromine ( ... ...

    Abstract The risk of accidental bromine (Br
    MeSH term(s) Administration, Inhalation ; Animals ; Behavior, Animal ; Biomarkers/metabolism ; Brain Injuries/pathology ; Brain Stem/pathology ; Bromine/administration & dosage ; Bromine/adverse effects ; Catecholamines/metabolism ; Female ; Glial Fibrillary Acidic Protein/metabolism ; Metabolome ; Neurons/drug effects ; Neurons/pathology ; Neurotransmitter Agents/metabolism ; Oxidative Stress/drug effects ; Rats, Sprague-Dawley ; Tryptophan Hydroxylase/metabolism ; Tyrosine 3-Monooxygenase/metabolism ; Rats
    Chemical Substances Biomarkers ; Catecholamines ; Glial Fibrillary Acidic Protein ; Neurotransmitter Agents ; Tyrosine 3-Monooxygenase (EC 1.14.16.2) ; Tryptophan Hydroxylase (EC 1.14.16.4) ; Bromine (SBV4XY874G)
    Language English
    Publishing date 2021-06-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms22126316
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  9. Article: Sex differences in cardiopulmonary effects of acute bromine exposure.

    Masjoan Juncos, Juan Xavier / Shakil, Shazia / Ahmad, Aamir / Mariappan, Nithya / Zafar, Iram / Bradley, Wayne E / Dell'Italia, Louis J / Ahmad, Aftab / Ahmad, Shama

    Toxicology research

    2021  Volume 10, Issue 5, Page(s) 1064–1073

    Abstract: Accidental occupational bromine (Br> ...

    Abstract Accidental occupational bromine (Br>
    Language English
    Publishing date 2021-08-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 2684701-2
    ISSN 2045-4538 ; 2045-452X
    ISSN (online) 2045-4538
    ISSN 2045-452X
    DOI 10.1093/toxres/tfab079
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  10. Article ; Online: Acute pulmonary effects of aerosolized nicotine.

    Ahmad, Shama / Zafar, Iram / Mariappan, Nithya / Husain, Maroof / Wei, Chih-Chang / Vetal, Nilam / Eltoum, Isam A / Ahmad, Aftab

    American journal of physiology. Lung cellular and molecular physiology

    2018  Volume 316, Issue 1, Page(s) L94–L104

    Abstract: Nicotine is a highly addictive principal component of both tobacco and electronic cigarette that is readily absorbed in blood. Nicotine-containing electronic cigarettes are promoted as a safe alternative to cigarette smoking. However, the isolated ... ...

    Abstract Nicotine is a highly addictive principal component of both tobacco and electronic cigarette that is readily absorbed in blood. Nicotine-containing electronic cigarettes are promoted as a safe alternative to cigarette smoking. However, the isolated effects of inhaled nicotine are largely unknown. Here we report a novel rat model of aerosolized nicotine with a particle size (~1 μm) in the respirable diameter range. Acute nicotine inhalation caused increased pulmonary edema and lung injury as measured by enhanced bronchoalveolar lavage fluid protein, IgM, lung wet-to-dry weight ratio, and high-mobility group box 1 (HMGB1) protein and decreased lung E-cadherin protein. Immunohistochemical analysis revealed congested blood vessels and increased neutrophil infiltration. Lung myeloperoxidase mRNA and protein increased in the nicotine-exposed rats. Complete blood counts also showed an increase in neutrophils, white blood cells, eosinophils, and basophils. Arterial blood gas measurements showed an increase in lactate. Lungs of nicotine-inhaling animals revealed increased mRNA levels of IL-1A and CXCL1. There was also an increase in IL-1α protein. In in vitro air-liquid interface cultures of airway epithelial cells, there was a dose dependent increase in HMGB1 release with nicotine treatment. Air-liquid cultures exposed to nicotine also resulted in a dose-dependent loss of barrier as measured by transepithelial electrical resistance and a decrease in E-cadherin expression. Nicotine also caused a dose-dependent increase in epithelial cell death and an increase in caspase-3/7 activities. These results show that the nicotine content of electronic cigarettes may have adverse pulmonary and systemic effects.
    MeSH term(s) Aerosols ; Animals ; Blood-Air Barrier/injuries ; Blood-Air Barrier/metabolism ; Blood-Air Barrier/pathology ; Caspase 3/metabolism ; Caspase 7/metabolism ; Chemokine CXCL1/blood ; HMGB1 Protein/metabolism ; Immunoglobulin M/blood ; Interleukin-1alpha/blood ; Leukocyte Count ; Male ; Neutrophil Infiltration/drug effects ; Neutrophils/metabolism ; Neutrophils/pathology ; Nicotine/adverse effects ; Nicotine/pharmacology ; Particle Size ; Pulmonary Edema/blood ; Pulmonary Edema/chemically induced ; Pulmonary Edema/pathology ; Rats ; Rats, Sprague-Dawley ; Vaping/adverse effects ; Vaping/blood ; Vaping/pathology
    Chemical Substances Aerosols ; Chemokine CXCL1 ; Cxcl1 protein, rat ; HMGB1 Protein ; Hbp1 protein, rat ; Immunoglobulin M ; Interleukin-1alpha ; Nicotine (6M3C89ZY6R) ; Casp3 protein, rat (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Caspase 7 (EC 3.4.22.-) ; Casp7 protein, rat (EC 3.4.22.60)
    Language English
    Publishing date 2018-10-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1013184-x
    ISSN 1522-1504 ; 1040-0605
    ISSN (online) 1522-1504
    ISSN 1040-0605
    DOI 10.1152/ajplung.00564.2017
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