Md Khadem Ali

All Publications

• Critical role for iron accumulation in the pathogenesis of fibrotic lung disease. The Journal of pathology Ali, M. K., Kim, R. Y., Brown, A. C., Donovan, C., Vanka, K. S., Mayall, J. R., Liu, G., Pillar, A. L., Jones-Freeman, B., Xenaki, D., Borghuis, T., Karim, R., Pinkerton, J. W., Aryal, R., Heidari, M., Martin, K. L., Burgess, J. K., Oliver, B. G., Trinder, D., Johnstone, D. M., Milward, E. A., Hansbro, P. M., Horvat, J. C. 2020

  Abstract

  Increased iron levels and/or dysregulated iron homeostasis occurs in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airways fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. We also show that iron accumulation is increased in lung sections from IPF patients and that human lung fibroblasts show greater proliferation, and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1+ macrophages that display altered phenotype in disease and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/path.5401

  View details for PubMedID 32083318

• Targeting BMPR2 Trafficking with Chaperones - An Important Step Towards Precision Medicine in Pulmonary Arterial Hypertension. American journal of respiratory cell and molecular biology Andruska, A., Ali, K., Spiekerkoetter, E. 2020

  View details for DOI 10.1165/rcmb.2020-0130ED

  View details for PubMedID 32339467

• Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma. The European respiratory journal Ali, M. K., Kim, R. Y., Brown, A. C., Mayall, J. R., Karim, R., Pinkerton, J. W., Liu, G., Martin, K. L., Starkey, M. R., Pillar, A., Donovan, C., Pathinayake, P. S., Carroll, O. R., Trinder, D., Tay, H. L., Badi, Y. E., Kermani, N. Z., Guo, Y. K., Aryal, R., Mumby, S., Pavlidis, S., Adcock, I. M., Weaver, J., Xenaki, D., Oliver, B. G., Holliday, E. G., Foster, P. S., Wark, P. A., Johnstone, D. M., Milward, E. A., Hansbro, P. M., Horvat, J. C. 2020

  Abstract

  Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma.We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild-moderate asthma patients and correlate with lower forced expiratory volume in 1?s (FEV1). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FEV1/FVC). The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TFR1) are increased in asthma with TFR1 expression correlating with reduced lung function and increased type 2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1+ macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma, including airway hyper-responsiveness and fibrosis and T2 inflammatory responses, in vivoTogether these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.

  View details for DOI 10.1183/13993003.01340-2019

  View details for PubMedID 32184317

• Delineating the molecular and histological events that govern right ventricular recovery using a novel mouse model of PA de-banding. Cardiovascular research Boehm, M., Tian, X., Mao, Y., Ichimura, K., Dufva, M. J., Ali, K., Prosseda, S. D., Shi, Y., Kuramoto, K., Reddy, S., Kheyfets, V. O., Metzger, R. J., Spiekerkoetter, E. 2019

  Abstract

  AIMS: The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload are unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodeling events.METHODS AND RESULTS: Surgical pulmonary artery banding (PAB) around a 26G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic and vascular myocardial remodeling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB) - after RV dysfunction and structural remodeling were established - initiated recovery of RV function (cardiac output, exercise capacity) along with rapid normalization in RV hypertrophy (RV/LV+S, cardiomyocyte area) and RV pressures (RVSP). RV fibrotic (collagen, elastic fibers, vimentin+ fibroblasts) and vascular (capillary density) remodeling were equally reversible, however reversal occurred at a later time-point after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators and apoptosis mediators as major cellular components underlying functional RV recovery.CONCLUSIONS: We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodeling events.TRANSLATIONAL PERSPECTIVE: The right ventricle (RV) in pulmonary arterial hypertension possesses a remarkable ability to recover after lung transplantation. Yet, some transplant centers prefer a heart-lung instead of lung transplantation when the RV function is severely impaired because knowledge is lacking whether fibrotic and vascular myocardial remodeling are completely reversible once the increased afterload burden is relieved. We have developed a mouse model to study gradual unloading of the RV and identified key molecular components and the timing of RV reverse-remodeling events with the ultimate goal to understand the RV recovery process and identify ways how to support the RV during recovery.

  View details for DOI 10.1093/cvr/cvz310

  View details for PubMedID 31738411

• IL-5/IL-13 drive NLRP3 inflammasome-mediated, steroid-resistant AHR in a model of obesity-associated asthma ERS International Congress 2019 abstracts James, P., Kim, R., Brown, A., Rae, B., Mayall, J., Ali, M., Starkey, M., Robertson, A., Wood, L., Cooper, M., O?Neill, ., Hansbro, P., Horvat, J. 2019

  View details for DOI 10.1183/13993003.congress-2019.PA3345

• Impaired induction of Slc26a4 promotes respiratory acidosis and severe, steroid-resistant asthma Kim, R., Pinkerton, J. W., Rae, B. E., Mayall, J. R., Brown, A. C., Nli, M., Goggins, B. J., Essilfie, A., Starkey, M. R., To, C., Bosco, A., Horvat, J. C., Hansbro, P. M. AMER ASSOC IMMUNOLOGISTS. 2017

  View details for Web of Science ID 000407750400106

• Role for dysregulated iron in the pathogenesis of murine models of lung disease Horvat, J. C., Ali, M., Johnstone, D., Kim, R. Y., Mayall, J. R., Karim, R., Pinkerton, J. W., Heidari, M., Martin, K. L., Donovam, C., Liu, G., Milward, E. A., Hansbro, P. M. AMER ASSOC IMMUNOLOGISTS. 2017

  View details for Web of Science ID 000407750400105

• HIGH FAT DIET-INDUCED OBESITY PROMOTES STEROID-RESISTANT ASTHMA THROUGH AN NLRP3 INFLAMMASOME-DEPENDENT MECHANISM Pinkerton, J., Kim, R., Mayall, J., Ali, M., Starkey, M., Robertson, A., O'Neill, L., Cooper, M., Hansbro, P., Horvat, J. WILEY. 2017: 65

  View details for Web of Science ID 000396791000117

• IMPAIRED INDUCTION OF SLC26A4 PROMOTES RESPIRATORY ACIDOSIS AND SEVERE, STEROID-INSENSITIVE ASTHMA Horvat, J., Pinkerton, J., Rae, B., Mayall, J., Brown, A., Ali, M., Goggins, B., Essilfie, A., Starkey, M., Bosco, A., Kim, R., Hansbro, P. WILEY. 2017: 65

  View details for Web of Science ID 000396791000118

• ROLE OF INCREASED IRON LEVELS IN THE PATHOGENESIS OF LUNG DISEASE Ali, M., Kim, R., Johnstone, D., Essilfie, A., Mayall, J., Karim, R., Pinkerton, J., Heidari, M., Donovan, C., Liu, G., Martin, K., Milward, L., Hansbro, P., Horvat, J. WILEY. 2017: 69

  View details for Web of Science ID 000396791000125

• Role of iron in the pathogenesis of respiratory disease. The international journal of biochemistry & cell biology Ali, M. K., Kim, R. Y., Karim, R., Mayall, J. R., Martin, K. L., Shahandeh, A., Abbasian, F., Starkey, M. R., Loustaud-Ratti, V., Johnstone, D., Milward, E. A., Hansbro, P. M., Horvat, J. C. 2017; 88: 181?95

  Abstract

  Iron is essential for many biological processes, however, too much or too little iron can result in a wide variety of pathological consequences, depending on the organ system, tissue or cell type affected. In order to reduce pathogenesis, iron levels are tightly controlled in throughout the body by regulatory systems that control iron absorption, systemic transport and cellular uptake and storage. Altered iron levels and/or dysregulated homeostasis have been associated with several lung diseases, including chronic obstructive pulmonary disease, lung cancer, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. However, the mechanisms that underpin these associations and whether iron plays a key role in the pathogenesis of lung disease are yet to be fully elucidated. Furthermore, in order to survive and replicate, pathogenic micro-organisms have evolved strategies to source host iron, including freeing iron from cells and proteins that store and transport iron. To counter these microbial strategies, mammals have evolved immune-mediated defence mechanisms that reduce iron availability to pathogens. This interplay between iron, infection and immunity has important ramifications for the pathogenesis and management of human respiratory infections and diseases. An increased understanding of the role that iron plays in the pathogenesis of lung disease and respiratory infections may help inform novel therapeutic strategies. Here we review the clinical and experimental evidence that highlights the potential importance of iron in respiratory diseases and infections.

  View details for DOI 10.1016/j.biocel.2017.05.003

  View details for PubMedID 28495571

• Impaired Induction Of Slc26a4 Promotes Respiratory Acidosis And Severe, Steroid-Insensitive Asthma Kim, R. Y., Pinkerton, J. W., Rae, B., Mayall, J. R., Brown, A. C., Ali, M., Goggins, B., Essilfie, A., Starkey, M. R., Bosco, A., Horvat, J. C., Hansbro, P. M. AMER THORACIC SOC. 2017

  View details for Web of Science ID 000400372502496

• Role Of Increased Iron Levels In The Pathogenesis Of Lung Disease Horvat, J. C., Alit, M., Johnstone, D., Essilfie, A., Mayall, J., Pinkerton, J. W., Donovan, C., Liu, G., Martina, K., Milward, A. E., Hansbro, P. M. AMER THORACIC SOC. 2017

  View details for Web of Science ID 000400372501706

• Role for NLRP3 Inflammasome-mediated, IL-1?-Dependent Responses in Severe, Steroid-Resistant Asthma. American journal of respiratory and critical care medicine Kim, R. Y., Pinkerton, J. W., Essilfie, A. T., Robertson, A. A., Baines, K. J., Brown, A. C., Mayall, J. R., Ali, M. K., Starkey, M. R., Hansbro, N. G., Hirota, J. A., Wood, L. G., Simpson, J. L., Knight, D. A., Wark, P. A., Gibson, P. G., O'Neill, L. A., Cooper, M. A., Horvat, J. C., Hansbro, P. M. 2017; 196 (3): 283?97

  Abstract

  Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1? responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma.To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1? in severe, steroid-resistant asthma.We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1? responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1? responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti-IL-1? antibody. Roles for IL-1?-induced neutrophilic inflammation were examined using IL-1? and anti-Ly6G.Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1? responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1? expression. Treatment with anti-IL-1?, Ac-YVAD-cho, and MCC950 suppressed IL-1? responses and the important steroid-resistant features of disease in mice, whereas IL-1? administration recapitulated these features. Neutrophil depletion suppressed IL-1?-induced steroid-resistant airway hyperresponsiveness.NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.

  View details for DOI 10.1164/rccm.201609-1830OC

  View details for PubMedID 28252317

• Investigating antioxidant therapy for steroid-resistant asthma Pinkerton, J., Kim, R., Essilfie, A., Rae, B., Mayall, J., Ali, M., Starkey, M., Wood, L., Biswal, S., Horvat, J., Hansbro, P. EUROPEAN RESPIRATORY SOC JOURNALS LTD. 2016

  View details for DOI 10.1183/13993003.congress-2016.PA570

  View details for Web of Science ID 000443059701120

• TARGETING OXIDATIVE STRESS FOR THE SUPPRESSION OF SEVERE, STEROID-INSENSITIVE ASTHMA Pinkerton, J., Kim, R., Essilfie, A., Rae, B., Mayall, J., Ali, M., Starkey, M., Wood, L., Biswal, S., Horvat, J., Hansbro, P. WILEY-BLACKWELL. 2016: 105

  View details for Web of Science ID 000373102400213

• Knockdown of the host cellular protein transportin 3 attenuates prototype foamy virus infection BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY Ali, M., Kim, J., Hamid, F., Shin, C. 2015; 79 (6): 943?51

  Abstract

  Transportin 3 (TNPO3) is a member of the importin-ß superfamily proteins. Despite numerous studies, the exact molecular mechanism of TNPO3 in retroviral infection is still controversial. Here, we provide evidence for the role and mechanism of TNPO3 in the replication of prototype foamy virus (PFV). Our findings revealed that PFV infection was reduced 2-fold by knockdown (KD) of TNPO3. However, late stage of viral replication including transcription, translation, viral assembly, and release was not influenced. The differential cellular localization of PFV integrase (IN) in KD cells pinpointed a remarkable reduction of viral replication at the nuclear import step. We also found that TNPO3 interacted with PFV IN but not with Gag, suggesting that IN-TNPO3 interaction is important for nuclear import of PFV pre-integration complex. Our report enlightens the mechanism of PFV interaction with TNPO3 and support ongoing research on PFV as a promising safe vector for gene therapy.

  View details for DOI 10.1080/09168451.2015.1008973

  View details for Web of Science ID 000356239400011

  View details for PubMedID 25660973

• Nuclear localization signals in prototype foamy viral integrase for successive infection and replication in dividing cells. Molecules and cells Hossain, A., Ali, K., Shin, C. G. 2014; 37 (2): 140?48

  Abstract

  We identified four basic amino acid residues as nuclear localization signals (NLS) in the C-terminal domain of the prototype foamy viral (PFV) integrase (IN) protein that were essential for viral replication. We constructed seven point mutants in the C-terminal domain by changing the lysine and arginine at residues 305, 308, 313, 315, 318, 324, and 329 to threonine or proline, respectively, to identify residues conferring NLS activity. Our results showed that mutation of these residues had no effect on expression assembly, release of viral particles, or in vitro recombinant IN enzymatic activity. However, mutations at residues 305 (R ? T), 313(R ? T), 315(R ? P), and 329(R ? T) lead to the production of defective viral particles with loss of infectivity, whereas non-defective mutations at residues 308(R ? T), 318(K ? T), and 324(K ? T) did not show any adverse effects on subsequent production or release of viral particles. Sub-cellular fractionation and immunostaining for viral protein PFV-IN and PFV-Gag localization revealed predominant cytoplasmic localization of PFV-IN in defective mutants, whereas cytoplasmic and nuclear localization of PFV-IN was observed in wild type and non-defective mutants. However sub-cellular localization of PFV-Gag resulted in predominant nuclear localization and less presence in the cytoplasm of the wild type and non-defective mutants. But defective mutants showed only nuclear localization of Gag. Therefore, we postulate that four basic arginine residues at 305, 313, 315 and 329 confer the karyoplilic properties of PFV-IN and are essential for successful viral integration and replication.

  View details for DOI 10.14348/molcells.2014.2331

  View details for PubMedID 24598999

  View details for PubMedCentralID PMC3935627

• Comparative sequence and expression analyses of African green monkey (Cercopithecus aethiops) TNPO3 from CV-1 cells GENES & GENOMICS Ali, M., Hossain, M., Shin, C. 2013; 35 (4): 549?58

  View details for DOI 10.1007/s13258-013-0102-8

  View details for Web of Science ID 000322725200015

• Structural and Functional Insights into Foamy Viral Integrase VIRUSES-BASEL Hossain, M., Ali, M., Shin, C. 2013; 5 (7): 1850?66

  Abstract

  Successful integration of retroviral DNA into the host chromosome is an essential step for viral replication. The process is mediated by virally encoded integrase (IN) and orchestrated by 3'-end processing and the strand transfer reaction. In vitro reaction conditions, such as substrate specificity, cofactor usage, and cellular binding partners for such reactions by the three distinct domains of prototype foamy viral integrase (PFV-IN) have been described well in several reports. Recent studies on the three-dimensional structure of the interacting complexes between PFV-IN and DNA, cofactors, binding partners, or inhibitors have explored the mechanistic details of such interactions and shown its utilization as an important target to develop anti-retroviral drugs. The presence of a potent, non-transferable nuclear localization signal in the PFV C-terminal domain extends its use as a model for investigating cellular trafficking of large molecular complexes through the nuclear pore complex and also to identify novel cellular targets for such trafficking. This review focuses on recent advancements in the structural analysis and in vitro functional aspects of PFV-IN.

  View details for DOI 10.3390/v5071850

  View details for Web of Science ID 000322172200016

  View details for PubMedID 23872492

  View details for PubMedCentralID PMC3738965