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Papers by Nithya mariappan

International Journal of Molecular Sciences

The risk of accidental bromine (Br2) exposure to the public has increased due to its enhanced ind... more The risk of accidental bromine (Br2) exposure to the public has increased due to its enhanced industrial use. Inhaled Br2 damages the lungs and the heart; however, adverse effects on the brain are unknown. In this study, we examined the neurological effects of inhaled Br2 in Sprague Dawley rats. Rats were exposed to Br2 (600 ppm for 45 min) and transferred to room air and cage behavior, and levels of glial fibrillary acidic protein (GFAP) in plasma were examined at various time intervals. Bromine exposure resulted in abnormal cage behavior such as head hitting, biting and aggression, hypervigilance, and hyperactivity. An increase in plasma GFAP and brain 4-hydroxynonenal (4-HNE) content also was observed in the exposed animals. Acute and delayed sympathetic nervous system activation was also evaluated by assessing the expression of catecholamine biosynthesizing enzymes, tryptophan hydroxylase (TrpH1 and TrpH2), and tyrosine hydroxylase (TyrH), along with an assessment of catecholami...

B105. MORE CALLS TO ACTION: AIR POLLUTION EXPOSURES AND HEALTH

Seminars in Cancer Biology, 2021

Inflammation is an essential component of several respiratory diseases, such as chronic obstructi... more 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.

Archives of Toxicology, 2020

Background: Highly reactive halogens such as bromine are more commonly utilized, leading to an in... more Background: Highly reactive halogens such as bromine are more commonly utilized, leading to an increase in quantities that are stocked and transported, therefore increasing the risk of accidental or deliberate exposure. Here we describe progression and potential mechanisms of adverse effects of a single injurious insult on the heart caused by bromine inhalation. Our studies have shown that bromine inhalation causes acute myocardial ischemia-reperfusion-like injury mediated by cytosolic calcium overload and increased calpain activity due to inactivation of SERCA. However, the progression of this injury in survivors is unknown. Our working hypothesis is that the initial injury causes irreversible damage that leads to chronic left ventricular systolic and diastolic dysfunction. Methods: Sprague Dawley rats received bromine exposure of 600 ppm for 45' and the survivors were sacrificed at 14 or 28 days, with matching naïve groups at each time point. Echocardiography, hemodynamic analysis, histology, electron microscopy and biochemical analysis of cardiac tissue were performed to assess functional, structural and molecular effects. Results: At 14 and 28 days, hemodynamic and echocardiographic analysis revealed increases in RV and LV end-diastolic pressure and LV end-diastolic wall stress with increased LV fibrosis at 28 days. TEM images demonstrated myofibrillar loss, cytoskeletal breakdown and mitochondrial damage at both time points. The myofibrillar damage and increased LV wall stress was reflected by increases in cTnI and NT-proBNP at both time points. LV shortening decreased as a function of increasing LV end-systolic wall stress and was accompanied by increased SERCA modification and a striking dephosphorylation of phospholamban with a significant increase in protein phosphatase 1. There was an increased 4-hydroxynonenal content in the myocardium at 28 days suggesting increased oxidative stress. Conclusions: These results indicate that the initial insult of bromine inhalation initiates a continuous process with chronic myocardial damage and subsequent LV systolic and diastolic dysfunction and that oxidative stress and phospholamban dephosphorylation play a central role.

C47. CRITICAL CARE: INSIGHTS FROM ANIMAL, EXPERIMENTAL, AND TRANSLATIONAL MODELS IN ARDS AND SEPSIS, 2020

Background: Extracellular nucleic acids (eNA) are increasingly being recognized as mediators of i... more Background: Extracellular nucleic acids (eNA) are increasingly being recognized as mediators of injury in a number of diseases. They are known to induce inflammation, coagulation and barrier dysfunction, which are characteristics of acute lung injury (ALI)/ Acute respiratory distress syndrome (ARDS). Inflammation and coagulation are key features in acid aspiration-induced ALI, but the factors that trigger inflammation and coagulation are unclear. Increased levels of eNA were observed in the bronchoalveolar lavage fluid (BALF) of ARDS patients and in a preclinical model of gastric aspiration (GA)-induced lung injury. To test whether targeting eNA can serve as a viable therapeutic strategy in treating ALI/ARDS, we evaluated the effect of eNA neutralization in a rat model of gastric aspiration. Methods: Rats (∼200 g) were exposed to gastric aspirate and two hours later eNA neutralizing agent was administered and animals were sacrificed 6 h post administration. eNA were isolated from BALF using a commercially available kit and nucleic acid concentration was measured. BALF was also collected for protein, IgM, high mobility group B1 (HMGB1) and cell counts. Arterial blood-gas measurements were also performed. Lung tissues were collected for gene expression evaluation. Results: To understand the role of increased levels of these eNA and whether they contribute to the pathogenesis, we sought to use scavengers of eNA in vivo. Increased eNA was observed in the BALF of rats instilled with GA. eNA neutralizing agent, when administered 2 h post GA also reduced levels of eNA. Neutralizing agent reversed GA-induced decrease in arterial pH and PaO2/FiO2 ratio. It diminished protein leak in the lung, attenuated inflammation as assessed by BALF HMGB1, a mediator of inflammation and inflammatory cytokines in the lung tissues. eNA neutralizing agent also reduced levels of lung tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) further indicating reduction in coagulation and subsequent airway obstruction. Conclusions: Our data clearly show that eNA play an important role in acid aspiration-induced ALI by stimulating systemic inflammation and coagulation contributing to lung damage. eNA neutralizing agent suppress inflammation and coagulation. Our results demonstrate a key role for eNA in the pathogenesis of ALI /ARDS and their neutralization can offer a novel therapeutic approach to treat ALI/ARDS.

Archives of Toxicology, 2020

Sulfur mustard (SM) is a highly toxic war chemical that causes significant morbidity and mortalit... more 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, 2h post exposure, reduced lung injury, inhibited disruption of alveolar-capillary barrier, improved blood oxygenation (PaO 2 /FiO 2 ratio), thus reversing ARDS symptoms. HDMBr treatment also reduced lung inflammation in the CEES-exposed animals by decreasing IL-6, IL-1A, CXCL-1 and CCL-2 mRNA levels in lung tissues and HMGB1 protein in BALF. Further, HDMBr treatment also reduced levels of lung tissue factor and plasminogen activator inhibitor-1 indicating reduction in clot formation and increased fibrinolysis. Fibrin was reduced in BALF of the HDMBr treated animals. This was further confirmed by histology that revealed diminished airway fibrin, epithelial sloughing and hyaline membrane in the lungs of HDMBr treated animals. HDMBr completely rescued the CEES-associated mortality 12h post-exposure when the survival rate in CEES-only group was just 50%. Experimental eNA treatment of cells caused increased inflammation that was reversed by HDMBr. These results demonstrate a role of eNA in the pathogenesis of CEES/SM-Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1 *

The FASEB Journal, 2019

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

American journal of physiology. Lung cellular and molecular physiology, Jan 25, 2018

Nicotine is a highly addictive principal component of both tobacco and electronic cigarette that ... more 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 micron) in the respirable diameter range. Acute nicotine inhalation caused increased pulmonary edema and lung injury as measured by enhanced bronchoalveolar lavage fluid (BALF) 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 (MPO) 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 m...

International Journal of Molecular Sciences

The risk of accidental bromine (Br2) exposure to the public has increased due to its enhanced ind... more The risk of accidental bromine (Br2) exposure to the public has increased due to its enhanced industrial use. Inhaled Br2 damages the lungs and the heart; however, adverse effects on the brain are unknown. In this study, we examined the neurological effects of inhaled Br2 in Sprague Dawley rats. Rats were exposed to Br2 (600 ppm for 45 min) and transferred to room air and cage behavior, and levels of glial fibrillary acidic protein (GFAP) in plasma were examined at various time intervals. Bromine exposure resulted in abnormal cage behavior such as head hitting, biting and aggression, hypervigilance, and hyperactivity. An increase in plasma GFAP and brain 4-hydroxynonenal (4-HNE) content also was observed in the exposed animals. Acute and delayed sympathetic nervous system activation was also evaluated by assessing the expression of catecholamine biosynthesizing enzymes, tryptophan hydroxylase (TrpH1 and TrpH2), and tyrosine hydroxylase (TyrH), along with an assessment of catecholami...

B105. MORE CALLS TO ACTION: AIR POLLUTION EXPOSURES AND HEALTH

Seminars in Cancer Biology, 2021

Inflammation is an essential component of several respiratory diseases, such as chronic obstructi... more 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.

Archives of Toxicology, 2020

Background: Highly reactive halogens such as bromine are more commonly utilized, leading to an in... more Background: Highly reactive halogens such as bromine are more commonly utilized, leading to an increase in quantities that are stocked and transported, therefore increasing the risk of accidental or deliberate exposure. Here we describe progression and potential mechanisms of adverse effects of a single injurious insult on the heart caused by bromine inhalation. Our studies have shown that bromine inhalation causes acute myocardial ischemia-reperfusion-like injury mediated by cytosolic calcium overload and increased calpain activity due to inactivation of SERCA. However, the progression of this injury in survivors is unknown. Our working hypothesis is that the initial injury causes irreversible damage that leads to chronic left ventricular systolic and diastolic dysfunction. Methods: Sprague Dawley rats received bromine exposure of 600 ppm for 45' and the survivors were sacrificed at 14 or 28 days, with matching naïve groups at each time point. Echocardiography, hemodynamic analysis, histology, electron microscopy and biochemical analysis of cardiac tissue were performed to assess functional, structural and molecular effects. Results: At 14 and 28 days, hemodynamic and echocardiographic analysis revealed increases in RV and LV end-diastolic pressure and LV end-diastolic wall stress with increased LV fibrosis at 28 days. TEM images demonstrated myofibrillar loss, cytoskeletal breakdown and mitochondrial damage at both time points. The myofibrillar damage and increased LV wall stress was reflected by increases in cTnI and NT-proBNP at both time points. LV shortening decreased as a function of increasing LV end-systolic wall stress and was accompanied by increased SERCA modification and a striking dephosphorylation of phospholamban with a significant increase in protein phosphatase 1. There was an increased 4-hydroxynonenal content in the myocardium at 28 days suggesting increased oxidative stress. Conclusions: These results indicate that the initial insult of bromine inhalation initiates a continuous process with chronic myocardial damage and subsequent LV systolic and diastolic dysfunction and that oxidative stress and phospholamban dephosphorylation play a central role.

C47. CRITICAL CARE: INSIGHTS FROM ANIMAL, EXPERIMENTAL, AND TRANSLATIONAL MODELS IN ARDS AND SEPSIS, 2020

Background: Extracellular nucleic acids (eNA) are increasingly being recognized as mediators of i... more Background: Extracellular nucleic acids (eNA) are increasingly being recognized as mediators of injury in a number of diseases. They are known to induce inflammation, coagulation and barrier dysfunction, which are characteristics of acute lung injury (ALI)/ Acute respiratory distress syndrome (ARDS). Inflammation and coagulation are key features in acid aspiration-induced ALI, but the factors that trigger inflammation and coagulation are unclear. Increased levels of eNA were observed in the bronchoalveolar lavage fluid (BALF) of ARDS patients and in a preclinical model of gastric aspiration (GA)-induced lung injury. To test whether targeting eNA can serve as a viable therapeutic strategy in treating ALI/ARDS, we evaluated the effect of eNA neutralization in a rat model of gastric aspiration. Methods: Rats (∼200 g) were exposed to gastric aspirate and two hours later eNA neutralizing agent was administered and animals were sacrificed 6 h post administration. eNA were isolated from BALF using a commercially available kit and nucleic acid concentration was measured. BALF was also collected for protein, IgM, high mobility group B1 (HMGB1) and cell counts. Arterial blood-gas measurements were also performed. Lung tissues were collected for gene expression evaluation. Results: To understand the role of increased levels of these eNA and whether they contribute to the pathogenesis, we sought to use scavengers of eNA in vivo. Increased eNA was observed in the BALF of rats instilled with GA. eNA neutralizing agent, when administered 2 h post GA also reduced levels of eNA. Neutralizing agent reversed GA-induced decrease in arterial pH and PaO2/FiO2 ratio. It diminished protein leak in the lung, attenuated inflammation as assessed by BALF HMGB1, a mediator of inflammation and inflammatory cytokines in the lung tissues. eNA neutralizing agent also reduced levels of lung tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) further indicating reduction in coagulation and subsequent airway obstruction. Conclusions: Our data clearly show that eNA play an important role in acid aspiration-induced ALI by stimulating systemic inflammation and coagulation contributing to lung damage. eNA neutralizing agent suppress inflammation and coagulation. Our results demonstrate a key role for eNA in the pathogenesis of ALI /ARDS and their neutralization can offer a novel therapeutic approach to treat ALI/ARDS.

Archives of Toxicology, 2020

Sulfur mustard (SM) is a highly toxic war chemical that causes significant morbidity and mortalit... more 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, 2h post exposure, reduced lung injury, inhibited disruption of alveolar-capillary barrier, improved blood oxygenation (PaO 2 /FiO 2 ratio), thus reversing ARDS symptoms. HDMBr treatment also reduced lung inflammation in the CEES-exposed animals by decreasing IL-6, IL-1A, CXCL-1 and CCL-2 mRNA levels in lung tissues and HMGB1 protein in BALF. Further, HDMBr treatment also reduced levels of lung tissue factor and plasminogen activator inhibitor-1 indicating reduction in clot formation and increased fibrinolysis. Fibrin was reduced in BALF of the HDMBr treated animals. This was further confirmed by histology that revealed diminished airway fibrin, epithelial sloughing and hyaline membrane in the lungs of HDMBr treated animals. HDMBr completely rescued the CEES-associated mortality 12h post-exposure when the survival rate in CEES-only group was just 50%. Experimental eNA treatment of cells caused increased inflammation that was reversed by HDMBr. These results demonstrate a role of eNA in the pathogenesis of CEES/SM-Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1 *

The FASEB Journal, 2019

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

American journal of physiology. Lung cellular and molecular physiology, Jan 25, 2018

Nicotine is a highly addictive principal component of both tobacco and electronic cigarette that ... more 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 micron) in the respirable diameter range. Acute nicotine inhalation caused increased pulmonary edema and lung injury as measured by enhanced bronchoalveolar lavage fluid (BALF) 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 (MPO) 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 m...