Day 1 :
Keynote Forum
Alexander D Verin
Augusta University
USA
Keynote: MAP kinases in endothelial permeability
Time : 10:00-10:45
Biography:
Dr. Verin has completed his Ph.D. at the age of 29 years from Moscow State University, Moscow Russia and postdoctoral studies from University of Indiana. Currently he is a Professor at Vascular Biology Center and Pulmonary Division at Augusta University, Augusta, GA. He has published more than 135 papers in reputed journals and serving as an academic editor of British Journal of Medicine and Medical Research and Cardiology and Angiology, and an editorial board member in several other journals in the field of pulmonary/cardiovascular research such as Cardiovascular Pharmacology, Journal of Multidisciplinary Pathology, Tissue Barriers, and World Journal of Respirology.
Abstract:
It is established that edema genic agonists (thrombin, LPS)-induced endothelial cell (EC) barrier dysfunction is tightly linked to myosin light chain (MLC)-dependent EC contraction and cytoskeletal reorganization. In this study, we examined the role of MAP kinases (p38 and p42/44) as potentially important enzymes in MLC-independent, agonist-mediated EC contractile responses and permeability. We demonstrated that thrombin significantly increased MAPK activities. Specific inhibition of p38 and p42/44 MAPK significantly attenuated thrombin-induced increases in F-actin stress fibers and permeability reflecting the involvement of MAPK in thrombin-mediated EC barrier compromise. Next, we examined potential cytoskeletal targets of thrombin-induced MAPK activation. MAPK inhibition did not alter basal and thrombin-induced EC MLC phosphorylation but significantly increased phosphorylation of caldesmon (Cad), an actin- and myosin-binding regulatory protein. Similar to smooth muscle, phosphorylation of Cad can potentially facilitate agonist-induced contraction and lead to EC barrier dysfunction. Under basal conditions Cad co-immunoprecipitated with actin and myosin suggesting a functional complex. Thrombin decreased the amount of myosin, but not actin in non-denaturing Cad immunoprecipitates suggesting decreased Cad/myosin interaction. Immunoblotting with anti-phospho Cad antibody to MAPK phosphorylation sites on Cad demonstrated that thrombin-mediated EC activation leads to direct phosphorylation of Cad by MAPK. Inhibition of MAPK significantly attenuated thrombin-induced Cad phosphorylation. These data strongly suggest the direct link between edema genic agonists-mediated EC contractile response and permeability, activation of MAPK cascades and Cad phosphorylation
Keynote Forum
Guozheng Wang
Liverpool University
UK
Keynote: Extracellular histone-induced acute lung injury
Time : 11:15-12:00
Biography:
Guozheng Wang MBChB, MD, Ph.D has both medical and biological backgrounds. After 12 years practice of internal medicine in Southeast University of China, full time biomedical research in UK Universities (including Cambridge, Oxford and Liverpool) has been performed for over 20 years. Current focus is on the pathophysiology, diagnosis, and therapy development of sepsis and other critical illnesses.
Abstract:
Although intra-nuclear histones play essential roles in DNA packaging and gene regulation, released histones following extensive cell or organ damage are toxic to pathogens but also to host hematopoietic, endothelial and epithelial cells. Cellular toxicity mainly results from direct membrane binding and resultant calcium influx with our work showing that this can directly trigger neutrophil MPO release and NETosis. In patients with severe trauma and sepsis, we found that high circulating histone levels correlated significantly to the incidence of acute lung injury (ALI) as well as markers of endothelial damage and coagulation activation. Using histone-infusion mouse models we showed that ALI with oedema, neutrophil congestion, NETs and thrombus formation impairs pulmonary microcirculation as indicated by pressure increase and even enlargement of right ventricle in extreme conditions. Since the lungs are the predominant sites of neutrophil margination and alveolar neutrophil infiltration is the hallmark of ALI, histone-induced neutrophil congestion, MPO release and NETs formation may provide an explanation as to why lungs are more susceptible to histone toxicity than other organs and new targets for managing ALI.
- Lung Cancer
Session Introduction
Ola El-Zammar
New York-Upstate Medical University
USA
Title: Usual interstitial pneumonia-Overview(UIP)
Time : 12:00-12.30
Biography:
Ola El-Zammar has completed her M.D. at the American University of Beirut in 1996 and then spent one year as an observer in the department of histopathology at the University Hospital of South Manchester in Washington. She then moved to the United States to complete her residency in anatomic and clinical pathology at Boston University school of Medicine and then at SUNY-Upstate. She completed a cytopathology fellowship and then a surgical pathology fellowship with pulmonary pathology focus with Dr Anna-Luise Katzenstein. She is now an assistant professor of pathology in the same department. She has published in the fields of gastrointestinal and pulmonary pathology in reputed journals.
Abstract:
Usual interstitial pneumonia (UIP) is the most common idiopathic interstitial pneumonia and the underlying histology in cases of idiopathic pulmonary fibrosis. It is a progressive disease with poor prognosis. For a long time, there has been no effective therapy but recent studies show promising response to pirfenidone and nintedanib. Accurate diagnosis is very important, especially for prognosis and transplant referral. This short overview will highlight the pathologic features of UIP, some important underlying causes, natural history, and acute exacerbation.
Shu-Lan Yeh
Chung Shan Medical University
Taiwan
Title: Combination of anticancer drugs with quercetin in human lung cancer cells
Time : 12:30-13:00
Biography:
Shu-Lan Yeh has obtained her PhD in Food Science and Biotechnology from National Chung Hsing University, Taiwan, in 2002. She became Assistant Professor in 2002 and became Professor in 2010 at Chung Shan Medical University, Taiwan. She has published more than 30 papers in reputed journals.
Abstract:
Recently, a combination of phytochemicals and anticancer drugs has been suggested as a potential strategy against cancer. The combined treatment may synergistically inhibit the growth of cancer cells and reduce the toxicity of chemotherapy due to the lower dose of each compound. Quercetin, a flavonoid, is ubiquitously found in various vegetarian foods. It is converted to its conjugated metabolites quickly after intake. Studies suggest that quercetin may enhance the antitumor effect of some chemotherapy drugs and decrease their adverse side effects. Our in vitro and in vivo study first showed that quercetin significantly increased the growth arrest and apoptosis induced by TSA through the p53-dependent pathway in human lung cancer A549 cells. Quercetin administrated intraperitoneally also enhanced the anti-tumor effect of TSA in tumor-bearing nude mice. Furthermore, we found that oral quercetin at high doses (1% quercetin containing diet) rather than low doses also significantly enhanced the antitumor effect of TSA in tumor-bearing nude mice. However, oral quercetin at all doses used decreased lymphocyte DNA damage and plasma lipid peroxidation induced by TSA in tumor bearing nude mice. Oral quercetin also had the potential to increased body weight, epididymal adipose and muscle in tumor bearing mice exposed to TSA. The effects were similar to that of quercetin given intraperitoneally. In addition, similar effects of quercetin administrated orally and intraperitoneally were observed in tumor bearing mice exposed to cisplatin. In conclusion, these studies demonstrate the potential of quercetin to enhance the antitumor effect of antitumor drugs and to decrease their side effects.
Vicki Chalker
Public Health England, London
UK
Title: Direct molecular typing to rapidly investigate cases and clusters of Legionnaires’ Disease in England and Wales
Time : 13:45-14:15
Biography:
Victoria Chalker has completed her PhD at Nottingham University and postdoctoral studies at the Royal Veterinary College. She is currently Head of the Respiratory and Systemic Bacteria Section, Bacterial Reference Department, Public Health England with remit for Legionella, non-vaccine preventable Streptococci, Leptospira and Molecules. She has published more than 40 papers in reputed journals and has been serves as a reviewer for several journals. She currently has 4 patents from her research.
Abstract:
Legionella pneumophila is the leading cause of Legionnaires’ disease (LD), a severe pneumonia that can occur as sporadic cases or point-source outbreaks affecting multiple patients. The infection is acquired by inhalation of aerosols from contaminated water systems. In order to identify the probable source and prevent further cases, clinical and environmental isolates are compared using phenotypic and genotypic methods. Typically up to 10 days are required to isolate L. pneumophila prior to the application of standard typing protocols. A rapid protocol using a real-time PCR specific for L. pneumophila and serogroup 1 combined with nested direct sequence based typing was adopted by Public Health England in 2012 to reduce reporting time for preliminary typing results. This rapid protocol was first used to investigate an outbreak that occurred in July/August 2012 and due to the positive feedback from that investigation, it was subsequently applied to other incidents in England and Wales where faster typing results would have aided incident investigation. We present here results from seven incidents that occurred between July 2012 and June 2015 where preliminary characterization of the infecting strain was possible in 1.58 days (SD 1.01) after sample receipt in contrast to 9.53 days (SD 3.73) when standard protocols were applied.
Alexander D Verin
Augusta University
USA
Title: Adenosine in lung endothelial barrier strengthening: role of Rac1 and MLCP signaling
Time : 14:15-14:45
Biography:
Dr. Verin has completed his Ph.D. at the age of 29 years from Moscow State University, Moscow Russia and postdoctoral studies from University of Indiana. Currently he is a Professor at Vascular Biology Center and Pulmonary Division at Augusta University, Augusta, GA. He has published more than 135 papers in reputed journals and serving as an academic editor of British Journal of Medicine and Medical Research and Cardiology and Angiology, and an editorial board member in several other journals in the field of pulmonary/cardiovascular research such as Cardiovascular Pharmacology, Journal of Multidisciplinary Pathology, Tissue Barriers, World Journal of Respirology
Abstract:
Endothelial cells (EC) form a semi-permeable barrier between the interior space of blood vessels and the underlying tissues. In acute lung injury (ALI) the EC barrier is weakened leading to increased permeability. The mechanisms that govern the highly clinically relevant process of increased EC permeability are under intense investigation. Little is known about the processes that determine barrier preservation/enhancement. Our data indicate that extracellular adenosine is able to protect and restore EC barrier in vitro and in vivo. We also demonstrated that adenosine induce activation of small GTPase, Rac 1 and this correlates with a significant attenuation of lipopolysaccharide (LPS)-induced EC permeability increase. Conversely, introduction of active Rac1 into EC strengthen EC barrier. In parallel, adenosine induces activation of myosin light chain (MLC) phosphatase (MLCP) and this also correlates with attenuation of LPS-induced EC permeability. In addition, we have shown that inhibition of MLCP leads to the phosphorylation of several cytoskeletal targets, which correlates with permeability increase suggesting that dephosphorylation of these proteins may be involved in the barrier-enhancing effect. Further, introduction of active MLCP subunits into the lung endothelium reduces LPS-induced lung inflammation strongly supporting the positive role of MLCP activity in EC barrier preservation against ALI in murine model. Therefore, the ability of adenosine to strengthen EC barrier appears to be dependent on Rac1 and MLCP activation. We speculate that adenosine-induced EC barrier preservation requires the coordinated activation of Rac1 and MLCP leading to EC cytoskeletal changes.
Imane Chaoui
Science and Nuclear Techniques (CNESTEN)
France
Title: The possible occurrence of Extensively Drug-Resistant Tuberculosis within Multidrug-Resistant Mycobacterium tuberculosis isolates from Morocco: retrospective study
Biography:
CHAOUI Imane has completed her PhD on Microbiology and molecular biology from Mohammed V University. She Is a researcher in the Centre national de l’énergie, des Sciences et techniques nucléaires in Morocco. Her work Is deeply related to tuberculosis research on: diagnostics, drug resistance, molecular epidemiology, investigations on the global TB transmission in Morocco and geo-localization of emerging and preexisting clones. She has published 9 papers in reputed journals and has been serving as a reviewver in many international journal.
Abstract:
Background: The emergence of extensively drug-resistant tuberculosis (XDR-TB) has raised public Heath concern for global control of TB. Although molecular characterization of drug resistance-associated mutations in multidrug-resistant isolates in Morocco has been made, mutations in XDR isolates and their genotypes have not been reported previously. Resistance to second line antituberculosis drugs (SLDs) Is mainly due to mutations in specific genes: gyrA and gyrB for resistance to fluoroquinolones (FQs), rrs, eis and tlyA for resistance to injectable drugs (kanamycin (KAN), amikacin (AMK), and capreomycin (CAP). Methods: A laboratory collection of 90 MTB isolates already characterized as MDR and 60 susceptible isolates randomly selected were enrolled in this retrospective study. The mutation profiles associated with resistance to SLDs: FQs and injectable drugs were assessed by DNA sequencing. Target sequences for four genes were examined: gyrA and gyrB (FQs), and rrs (KAN, AMK, and CAP) and tlyA (CAP). All samples had their fingerprint already established by spoligotyping. Results: Molecular analysis showed that 26.7% of MDR isolates are pre-XDR strains and harbored mutations in gyrA gene. The Most prevalent mutations involved in FQ resistance was Asp94Gly (50%). None of the isolates harbored mutations neither in gyrB nor in rrs genes. The sensitivity for the detection of FQs resistance by DNA sequencing could not be evaluated because of the lack of the information regarding DST for SLDs. All pre-XDR strains belong to LAM Lineage (LAM4 and LAM9) raising the possible emergence of a specific clone. Conclusion: The results of this préliminaire study highlight the need for rapid detection of mutations associated with resistance to SLDs in order to adjust timely the treatment and to interrupt the propagation of virtually untreatable form of the diseuse. Keywords: Morocco, Mycobacterium tuberculosis, extremely drug resistant, gyrA, gyrB, rrs, tlyA, sequencing
- COPD and Respiratory Disorders
Session Introduction
Shakila Devi Perumal
St. Michaels Hospital
Ireland
Title: A Simple Tool to Promote Physical Activity in Patients with COPD
Time : 14:45-15:15
Biography:
Shakila Devi Perumal is a Pulmonary Rehabilitation Coordinator in St. Michaels Hospital, part of St. Vincent’s Healthcare Group since 2007. She holds a Bachelor of Physiotherapy (Dr. MGR Medical University, India), M S Psychotherapy and Counseling (IPMS, India), Higher Diploma in Respiratory Physiotherapy from Trinity College of Dublin. She is an expert in pulmonary rehabilitation. Her main research interests include the rehabilitation of patients with chronic obstructive pulmonary disease, asthma and pulmonary fibrosis, with emphasis on physical activity and sleep. She has presented her research at national and international conferences. Recently, she was honored with a best poster award in the 2nd International Lung Workshop and it was endorsed by European Respiratory Society. She is an active member in Irish Society of Chartered Physiotherapist and European Respiratory Society.
Abstract:
Physical inactivity is a prominent feature in patients with chronic obstructive pulmonary disease (COPD) compared to age matched healthy subjects or with any other people with chronic disease. Physical inactivity predicts poor outcomes in COPD and hastens the disease progression. Pulmonary rehabilitation has been endorsed as an effective non-pharmacological therapy to enhance exercise capacity and quality of life in patients with COPD, yet its effects on promotion of physical activity is unknown. Furthermore, the recent international guidelines on pulmonary rehabilitation emphasize on “long-term health enhancing behavior change” and increase in physical activity is considered to enhance positive health benefits in COPD. However, physical activity is perceived as a complex behavior difficult to reverse. We have explored the effects of ground walking prescription to promote physical activity in patients with COPD and observed significant improvements in physical activity and other outcomes of pulmonary rehabilitation.
Rogelio Hernández Pando
Metropolitan Autonomous University
USA
Title: The hepatocyte growth factor prevents hepatotoxicity induced by the administration of therapeutically suprapharmacological doses of isoniazid and rifampicin in a model of murine multidrug resistant pulmonary tuberculosis
Time : 15:15-15:45
Biography:
Rogelio Hernandez-Pando in to Experimental Pathology Section is working under Department of Pathology at National Institute of Medical Sciences and Nutrition in Mexico City.
Abstract:
Tuberculosis (TB) is a worldwide health problem. The World Health Organization (WHO) informed that there were 9.6 million new active cases and 1.5 million deaths during 2014.Although TB can be controlled and cured by chemotherapy, treatment usually requires four specific antibiotics during 6 months, and the most efficient drugs isoniazid (INH) and rifampicin (RIF) frequently produce liver damage. This long and toxic effect of TB treatment produces significant compliance problems. The consequence of this is disease recurrence and the arising of multi drug resistant (MDR) strains. During the last years MDR have increased their frequency, in 2014 MDR TB afflicted around 480,000 people worldwide and produced 190,000 deaths. Treatment of MDR-TB is resource intensive and requires second line drugs which are more expensive, toxic, and less effective than primary drugs. These problems have motivated the search for new drugs and treatment strategies. MDR strains have a drug-resistance threshold, high concentrations of INH and RIF can kill MDR bacilli but these suprapharmacological doses of antibiotics produce severe liver damage. Hepatocyte growth factor (HGF) is a multitask growth factor that stimulates both ant apoptotic and antioxidant responses that counteract the toxic effects of drug metabolism in the liver. We previously showed that recombinant HGF (iv) prevented all the harmful effects of INH and RIF by increasing the activation of Erk1/2 and PKCδ signaling pathways and glutathione (GSH) synthesis. In this study BALB/c mice were infected intra-tracheally with a high dose of MDR clinical isolate resistant to all primary drugs, after 3 months of infection when mice suffered extensive progressive pulmonary TB animals were treated with suprapharmacological doses of INH and RIF by intragastric or intra-tracheal route in combination with recombinant HGF (IP). Particularly the intratracheal treatment produced a significant decrease of pulmonary bacillary loads in coexistence with less tissue damage in the lungs (pneumonia) and in the liver (esteatosis, necrosis). This is a novel scheme of treatment of MDR-TB that uses high doses of conventional chemotherapy but with the addition of a liver protector which is HGF.
Imane Chaoui
Science and Nuclear Techniques (CNESTEN)
France
Title: The possible occurrence of Extensively Drug-Resistant Tuberculosis within Multidrug-Resistant Mycobacterium tuberculosis isolates from Morocco: retrospective study
Time : 15:45-16:15
Biography:
CHAOUI Imane has completed her PhD on Microbiology and molecular biology from Mohammed V University. She Is a researcher in the Centre national de l’énergie, des Sciences et techniques nuclearizes in Morocco. Her work Is deeply related to tuberculosis research on: diagnostics, drug resistance, molecular epidemiology, investigations on the global TB transmission in Morocco and geo-localization of emerging and preexisting clones. She has published 9 papers in reputed journals and has been serving as a reviewer in many international journals.
Abstract:
Background: The emergence of extensively drug-resistant tuberculosis (XDR-TB) has raised public Heath concern for global control of TB. Although molecular characterization of drug resistance-associated mutations in multidrug-resistant isolates in Morocco has been made, mutations in XDR isolates and their genotypes have not been reported previously. Resistance to second line antituberculosis drugs (SLDs) Is mainly due to mutations in specific genes: gyrA and gyrB for resistance to fluoroquinolones (FQs), rrs, eis and tlyA for resistance to injectable drugs (kanamycin (KAN), amikacin (AMK), and capreomycin (CAP). Methods: A laboratory collection of 90 MTB isolates already characterized as MDR and 60 susceptible isolates randomly selected were enrolled in this retrospective study. The mutation profiles associated with resistance to SLDs: FQs and injectable drugs were assessed by DNA sequencing. Target sequences for four genes were examined: gyrA and gyrB (FQs), and rrs (KAN, AMK, and CAP) and tlyA (CAP). All samples had their fingerprint already established by spoligotyping. Results: Molecular analysis showed that 26.7% of MDR isolates are pre-XDR strains and harbored mutations in gyrA gene. The Most prevalent mutations involved in FQ resistance was Asp94Gly (50%). None of the isolates harbored mutations neither in gyrB nor in rrs genes. The sensitivity for the detection of FQs resistance by DNA sequencing could not be evaluated because of the lack of the information regarding DST for SLDs. All pre-XDR strains belong to LAM Lineage (LAM4 and LAM9) raising the possible emergence of a specific clone. Conclusion: The results of this préliminaire study highlight the need for rapid detection of mutations associated with resistance to SLDs in order to adjust timely the treatment and to interrupt the propagation of virtually untreatable form of the diseuse. Keywords: Morocco, Mycobacterium tuberculosis, extremely drug resistant, gyrA, gyrB, rrs, tlyA, sequencing
Nobuyuki Nosaka
Okayama University
Japan
Title: Therapeutic Effects of Anti-High Mobility Group Box-1 Monoclonal Antibody for Influenza A virus (H1N1) – Induced Pneumonia
Time : 16:45-17:15
Biography:
N. Nosaka is a young physician scientist specialized in pediatric critical care. He has just completed his PhD this year from Okayama University, Japan. T. Morishima is a leading researcher specialized in pediatric infectious diseases. He was a professor of the department of Pediatrics, Okayama University, Japan from 2004 to 2014. His contibution is enormous in the field of severe influenza infection in Japan.
Abstract:
Background: Provision for the emergence of influenza pandemic is an urgent issue. The discovery of a novel anti-influenza therapeutic approach would increase the effectiveness of traditional virus-based strategies. High mobility group box-1 (HMGB1) plays an important role in triggering inflammatory responses in many types of diseases, including influenza. Objective: This study was undertaken to evaluate therapeutic effects of anti-HMGB1 monoclonal antibody (mAb) for influenza A virus (H1N1) – induced pneumonia. Method: Influenza A pneumonia was induced in nine-week-old male C57BL/6 mice by inoculation with influenza virus A/Puerto Rico/8/34 (H1N1). Anti-HMGB1 mAb or control mAb was administered intravenously at 1, 24 and 48 hours after inoculation. Survival rate was analyzed. Lung lavage and pathological analysis were performed on days 3, 5, 7 and 10 after inoculation. Result: Anti-HMGB1 mAb significantly improved the survival rate of H1N1-inoculated mice, although the treatment did not affect virus propagation in the lung. The treatment significantly attenuated the histological changes and neutrophil infiltration in the lung of H1N1-inoculated mice; these were associated with inhibition of HMGB1 and suppression of inflammatory cytokine/chemokine expression and oxidative stress enhancement. Conclusion: Anti-HMGB1 mAb may provide a novel and effective pharmacological strategy for severe influenza virus infection in humans by reducing the inflammatory responses induced by HMGB1.
Michele R. Pedicone
University of Washington
USA
Title: Application of Non Invasive Neurally Adujusted Ventilatory Assist (NAVA) in the Very Low Birth Weight Infant A review and case study presentation
Time : 17:15-17:45
Biography:
Michele Pedicone completed a Masters of Science in Respiratory Care Leadership and Education from Northeastern University in Boston, MA and is currently pursuing a Doctoral degree in Global Health Studies at Nova Southeastern University in Fort Lauderdale, FL. She practices respiratory care at the University of Washington Neonatal Intensive Care Unit in Seattle, WA and is an instructor at Seattle Central College also located in Seattle. She is active in the Respiratory Care Society of Washington, having served as Vice-President and for the American Association for Respiratory Care as a member of the Political Advocacy Team.
Abstract:
Mechanical ventilation for the very low birth weight infant has traditionally involved either pressure or volume-breath types. Modern microprocessor ventilators are capable of delivering hybrid modes which can combine volume and pressure. NAVA takes a unique approach to mechanical ventilation, delivering assistance in proportion to and synchrony with the patients’ own respiratory efforts. The electrical activity of the diaphragm (EAdi) is captured via an indwelling catheter, this EAdi signal allows for synchronization of the ventilator to the infant's own breathing effort. Synchrony is possible even in the presence of air leak, making this mode a successful choice in the neonate population, both invasively and non-invasively. Intubation has potential harmful results for the very low birth weight infant, to include tracheal trauma and infection. In an attempt to minimize these risks, non invasive NAVA has allowed for the synchronous ventilation of very low birth weight infants. A review of the use of non invasive NAVA and case studies from a Level IV Neonatal Intensive Care Unit (NICU) will be presented.
Guozheng Wang
Liverpool University
UK
Title: Circulating histone-induced acute lung injury
Time : 17:45-18:15
Biography:
Guozheng Wang has both medical and biological backgrounds. He practiced internal medicine in China for 12 years and has been performing full time biomedical research in UK Universities (Cambridge, Oxford and Liverpool) for over 20 years.
Abstract:
Although intra-nuclear histones play essential roles in DNA packaging and gene regulation, released histones following extensive cell or organ damage are toxic to pathogens but also to host hematopoietic, endothelial and epithelial cells. Cellular toxicity mainly results from direct membrane binding and resultant calcium influx with our work showing that this can directly trigger neutrophil MPO release and NETosis. In patients with severe trauma and sepsis, we found that high circulating histone levels correlated significantly to the incidence of acute lung injury (ALI) as well as markers of endothelial damage and coagulation activation. Using histone-infusion mouse models we showed ALI with oedema, neutrophil congestion, NETs and thrombus formation, which thereby impair pulmonary microcirculation as indicated by pressure increase and even enlargement of right ventricle in extreme conditions. As the lungs are the predominant sites of neutrophil margination and alveolar neutrophil infiltration is the hallmark of ALI, histone-induced neutrophil cogestion, MPO release and NETs formation may provide an explanation as to why lungs are more susceptible to histone toxicity than other organs.