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An Immune Basis for Lung Parenchymal Destruction in Chronic Obstructive Pulmonary Disease and Emphysema
Open accessAbstract
BACKGROUND: Chronic obstructive pulmonary disease and emphysema are a frequent result of long-term smoking, but the exact mechanisms, specifically which types of cells are associated with the lung destruction, are unclear. METHODS AND FINDINGS: We studied different subsets of lymphocytes taken from portions of human lungs removed surgically to find out which lymphocytes were the most frequent, which cell-surface markers these lymphocytes expressed, and whether the lymphocytes secreted any specific factors that could be associated with disease. We found that loss of lung function in patients with chronic obstructive pulmonary disease and emphysema was associated with a high percentage of CD4+ and CD8+ T lymphocytes that expressed chemokine receptors CCR5 and CXCR3 (both markers of T helper 1 cells), but not CCR3 or CCR4 (markers of T helper 2 cells). Lung lymphocytes in patients with chronic obstructive pulmonary disease and emphysema secrete more interferon gamma--often associated with T helper 1 cells--and interferon-inducible protein 10 and monokine induced by interferon, both of which bind to CXCR3 and are involved in attracting T helper 1 cells. In response to interferon-inducible protein 10 and monokine induced by interferon, but not interferon gamma, lung macrophages secreted macrophage metalloelastase (matrix metalloproteinase-12), a potent elastin-degrading enzyme that causes tissue destruction and which has been linked to emphysema. CONCLUSIONS: These data suggest that Th1 lymphoctytes in the lungs of people with smoking-related damage drive progression of emphysema through CXCR3 ligands, interferon-inducible protein 10, and monokine induced by interferon.
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“Specifically, macrophages, which can produce multiple proinflammatory cytokines and secrete MMPs, are the most abundant cell type in the BAL fluid of COPD patients, and increased numbers correlate with disease severity (85, 86, 104).”
From Aging and Lung Disease (2020) · cites this paper as [85]
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“Impaired phagocytosis and clearance of cellular debris by airway macrophages in COPD result in persistent inflammation (85, 104).”
From Aging and Lung Disease (2020) · cites this paper as [85]
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“Pulmonary lymphocytes isolated from emphysematous lung tissue are frequently activated (Sullivan et al 2005) and capable of secreting mediators that have been implicated in the pathogenesis of COPD (Grumelli et al 2004).”
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Kapellos, T. S., Bassler, K. E., Aschenbrenner, A. C., Fujii, W., & Schultze, J. L. (2018) · Journal of Immunology Research · doi:10.1155/2018/2349045 · Cited by 87
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“Lunginfiltrated CD8+CTLs induce the cell death of alveolar epithelial cells either directly, through the secretion of cytotoxic molecules (TNF-α, perforins, and granzymes), or indirectly, through the production of IFN-γ or IL-17 which promotes tissue destruction by promoting the secretion of matrix metalloproteinases…”
BackgroundChronic Bronchitis and Emphysema
Shapiro, S. D., Reilly, J. J., & Rennard, S. I. (2010) · Elsevier eBooks · doi:10.1016/b978-1-4160-4710-0.00039-0 · Cited by 80
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“However, the immune response seen in smokers compared to in nonsmokers is different from what we expect to find in a tumor (Grumelli et al., 2004; Shaykhiev et al., 2009), and when samples from normal lung were clustered together with tumor samples based on immune cell estimates, these did not cluster with their paire…”
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“Currently significant research focus and pharmaceutical company direction is geared towards the discovery of effective anti-inflammatory therapeutic targets given the minimal efficacy of existing treatments [4].”
BackgroundMatrix Metalloproteinase-2 Protein in Lung Periphery Is Related to COPD Progression
Baraldo, S., Bazzan, E., Zanin, M. E., Turato, G., Garbisa, S., Maestrelli, P., Papi, A. A., Miniati, M., Fabbri, L. M., Zuin, R., et al. (2007) · CHEST Journal · doi:10.1378/chest.06-2819 · Cited by 81
Aspects on pathophysiological mechanisms in COPD
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Lung CD8+ T cells in COPD have increased expression of bacterial TLRs
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“Collectively, our findings support previous studies [33-37] on the importance of adaptive immune responses in emphysematous lung destruction.”
ResultAgonistic induction of PPARγ reverses cigarette smoke–induced emphysema
Shan, M., You, R., Yuan, X., Frazier, M. V., Porter, P., Seryshev, A. B., Hong, J.-S., Song, L., Zhang, Y., Hilsenbeck, S. G., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci70587 · Cited by 79
“Macrophages and mDCs comprise some of the most abundant inflammatory cells in the lungs of smokers and in response to IL-17A can express proteolytic enzymes (e.g., MMP12 and MMP9) that are strongly associated with emphysema (3, 11, 30).”
Self-citationAksoy, M. O., Yang, Y., Ji, R., Reddy, P. J., Shahabuddin, S., Litvin, J., Rogers, T. J., & Kelsen, S. G. (2005) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00430.2005 · Cited by 78
“In particular, the CXC chemokine receptor CXCR3 (21, 22) is highly expressed by T lymphocytes of the Th1/Tc1 phenotype, natural killer cells (NK cells), dendritic cells, mast cells, alveolar macrophages, and eosinophils (7, 10, 13, 16, 21, 26).”
BackgroundEnhanced monocyte migration to CXCR3 and CCR5 chemokines in COPD
da Costa, C. H., Traves, S. L., Tudhope, S. J., Fenwick, P. S., Belchamber, K. B. R., Russell, R. E. K., Barnes, P. J., & Donnelly, L. (2016) · European Respiratory Journal · doi:10.1183/13993003.01642-2015 · Cited by 78
COPD as a Disease of Immunosenescence
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“Th1 cells secrete interferon gamma and Th17 releases IL-17, thus leading to increased inflammation at the site of injury in response to cigarette exposure.(23,24) In addition, smokers with COPD have significantly fewer T-regulatory cells in the lungs; this may contribute to the perpetuation of inflammation and the ind…”
BackgroundNontypeable Haemophilus influenzae in chronic obstructive pulmonary disease and lung cancer
Moghaddam, S. J. (2011) · International Journal of COPD · doi:10.2147/copd.s15417 · Cited by 75
“CCR5 and CXCR3 (markers of Th1 cells), but not CCR3 or CCR4 (markers of Th2 cells).(33,34) CD8+ cells are typically”
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“Indirect mechanisms, whereby lymphocyte activation contributes to COPD, are based on data that indicate production of Th1 cytokines, such as IFN-g, is increased in T cells of patients with COPD (34, 47).”
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Pneumocystis: A Novel Pathogen in Chronic Obstructive Pulmonary Disease?
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“The latter finding was unexpected because we and others have previously shown that the lung immune phenotype of subjects with stable COPD and emphysema is highly TH1 biased and that T cells extracted from the lungs of patients with COPD and emphysema specifically do not secrete IL-4.”
ResultSelf-citationHoffmann, R. F., Jonker, M. R., Brandenburg, S. M., de Bruin, H. G., ten Hacken, N. H. T., van Oosterhout, A. J. M., & Heijink, I. H. (2019) · Scientific Reports · doi:10.1038/s41598-019-51517-x · Cited by 71
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“Furthermore, viruses are a major cause of COPD exacerbations, and the levels of IFN-g are increased in COPD patients during virus-triggered exacerbations (Grumelli et al., 2004; Makris et al., 2008; Singh et al., 2010).”
Role of Apoptosis in Amplifying Inflammatory Responses in Lung Diseases
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Pathogenesis of Inflammation and Repair in Advanced COPD
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“These CD4þ cells are activated and appear to be of a Th1 subtype because they express IFN-gamma and CXCR3.(20,21) Like CD8þ cells, CD4þ cell numbers in the lung correlate directly with disease severity.”
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Differences in systemic inflammation between cigarette and biomass smoke-induced COPD
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“Th1 lymphocytes have been implicated in the pathogenesis of smoking-related emphysema.(21) On the other side, in asthma, there is a predominance of Th2 cells.”
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“Pulmonary macrophages are able to induce airway smooth muscle contraction, which leads to airway hyperresponsiveness by inducing histamine release from basophils and mast cells [176], by impairing airway-adrenergic function through the production of oxygen radicals [53], and by increasing the function of”
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Overexpression of Methyl-CpG Binding Protein 2 Impairs T H 1 Responses
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Self-citationProteases and Their Inhibitors in Chronic Obstructive Pulmonary Disease
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BackgroundInfluentialThe cellular and molecular determinants of emphysematous destruction in COPD
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BackgroundA Role for Matrix Metalloproteinase 9 in IFNγ-Mediated Injury in Developing Lungs
Harijith, A. K., Choo-Wing, R., Çataltepe, S., Yasumatsu, R., Aghai, Z. H., Janér, J., ANDERSSON, S. M., Homer, R., & Bhandari, V. (2011) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2010-0058oc · Cited by 60
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“Plasma concentrations of soluble Fas were associated with the % DLCO, whereas CXCL9/monokine induced by interferon-γ (CXCL9/Mig), granulocyte- colony stimulating factor (G-CSF) and IL13 showed inverse relationships with the % DLCO.”
InfluentialXu, Y., Li, J., Lin, Z., Liang, W., Qin, L., Ding, J., Chen, S., & Zhou, L. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.860362 · Cited by 56
“However, T lymphocytes also mediate cell death directly via the production of cytotoxic mediators and secretion of Fas (Grumelli et al., 2004; Gadgil and Duncan, 2008).”
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“MMP-9 and -12, in particular, have been implicated in COPD because the expression of these proteinases is elevated in the lungs of COPD patients and appear to localize to areas of the lung that are diseased (Segura-Valdez et al., 2000; Grumelli et al., 2004).”
Backgroundp38 MAPK signaling in chronic obstructive pulmonary disease pathogenesis and inhibitor therapeutics
Ahmadi, A., Ahrari, S., Salimian, J., Salehi, Z., Karimi, M., Emamvirdizadeh, A., Jamalkandi, S. A., & Ghanei, M. (2023) · Cell Communication and Signaling · doi:10.1186/s12964-023-01337-4 · Cited by 59
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Esmaeil, N., Gharagozloo, M., Rezaei, A., & Grünig, G. (2014) · Europe PMC (PubMed Central) · Cited by 55
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Secretory Leucocyte Protease Inhibitor Inhibits Interferon-γ-induced Cathepsin S Expression
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“On the other hand, CXCL9 and CXCL10, by binding to CXCR3 chemokine receptor present on macrophage surface, are able to induce MMP-12 secretion [58,75].”
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A hypothesis for the initiation of COPD
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ROLE FOR CATHEPSIN K IN EMPHYSEMA IN SMOKE-EXPOSED GUINEA PIGS
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“Multiple studies indicate that lung inflammation is a hallmark of smoke-induced emphysema [16,17,18].”
Matrix remodeling in chronic lung diseases
Gu, B., Madison, M. C., Corry, D. B., & Kheradmand, F. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.03.012 · Cited by 52
“Here, we describe the roles of collagen and its associated fragments in the pathogenesis of idiopathic pulmonary fibrosis, COPD, and asthma.”
BackgroundInfluentialSelf-citationRojas, J., Ochsner, S. A., New, F., Divakar, P., Yang, C. X., Wu, T. D., Robinson, J. W., Chandrashekar, D. S., Banovich, N. E., Rosas, I. O., et al. (2023) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202303-0507le · Cited by 50
“The emphysematous lung is characterized by off-targeted immune responses contributing to parenchymal damage (3, 4).”
BackgroundSelf-citationSolleiro-Villavicencio, H., Quintana-Carrillo, R., Falfán‐Valencia, R., & Vargas-Rojas, M. I. (2015) · Clinical Immunology · doi:10.1016/j.clim.2015.07.009 · Cited by 50
Kwon, B., Hong, S., Shin, K., Choi, E., Hwang, J.-J., & Lee, S. (2013) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201302-0295oc · Cited by 49
Bhavani, S. V., Tsai, C., Perusich, S., Hesselbacher, S. E., Coxson, H. O., Pandit, L. M., Corry, D. B., & Kheradmand, F. (2015) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201504-0736oc · Cited by 49
“by type 1 and 17 cytokines in emphysema as we previously demonstrated, specifically, their role in up-regulating elastolytic matrix metalloproteinase activity (23, 25) Conversely, in former smokers, we found a negative association between IFN-g production and emphysema progression, whereas IL-6 did not reach statistic…”
BackgroundSelf-citationInnate immunity proteins in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis
Tsoumakidou, M., Bouloukaki, I., Thimaki, K., Tzanakis, N., & Siafakas, N. M. (2010) · Experimental Lung Research · doi:10.3109/01902141003690389 · Cited by 48
“Both Th1 immunity and DC numbers have been shown to be increased in COPD [17, 18].”
BackgroundLimjunyawong, N., Craig, J. M., Lagassé, H. A. D., Scott, A. L., & Mitzner, W. (2015) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00214.2015 · Cited by 48
Freeman, C. M., Crudgington, S., Stolberg, V. R., Brown, J. P., Sonstein, J., Alexis, N. E., Doerschuk, C. M., Basta, P. V., Carretta, E. E., Couper, D. J., et al. (2015) · Journal of Translational Medicine · doi:10.1186/s12967-014-0374-z · Cited by 48
“especially of emphysema, in multiple studies [14-19].”
Liu, Y., Kheradmand, F., Davis, C., Scheurer, M. E., Wheeler, D. A., Tsavachidis, S., Armstrong, G., Simpson, C. L., Mandal, D. M., Kupert, E. Y., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2015.09.015 · Cited by 48
Self-citationExperimental Therapeutics of Nrf2 as a Target for Prevention of Bacterial Exacerbations in COPD
Biswal, S. S., Thimmulappa, R. K., & Harvey, C. J. (2012) · Proceedings of the American Thoracic Society · doi:10.1513/pats.201201-009ms · Cited by 47
“CD4(1) Th1 cells secrete IFN-g and augment innate immune responses (7).”
BackgroundO’Connell, D., Bouazza, B., Kokalari, B., Amrani, Y., Khatib, A., Ganther, J. D., & Tliba, O. (2015) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00099.2015 · Cited by 46
“Similarly, an increase in IFNγ levels 89 has been observed in patients with chronic obstructive pulmonary disease (COPD) and 90 emphysema, two chronic inflammatory airway diseases associated with a high rate of GC 91 insensitivity (14, 25).”
BackgroundEppert, B. L., Wortham, B. W., Flury, J. L., & Borchers, M. T. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1202442 · Cited by 46
“CD4 T cells in the lungs of COPD patients are skewed toward a Th1 phenotype, and T cell–derived cytokines were linked to the expression of proteases by macrophages (13).”
BackgroundPerforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema
Morissette, M. C., Parent, J., & Milot, J. (2007) · Respiratory Research · doi:10.1186/1465-9921-8-62 · Cited by 45
“[32] also showed that lymphocytes isolated from the lung of emphysematous subjects express higher levels of CCR5, another Th1 receptor, and of CXCR3 than those of normal subjects.”
BackgroundAttenuation of acute lung inflammation induced by cigarette smoke in CXCR3 knockout mice
Nie, L., Xiang, R., Zhou, W., Lu, B., Cheng, D., & Gao, J. (2008) · Respiratory Research · doi:10.1186/1465-9921-9-82 · Cited by 45
“CXCL10, a CXCR3 ligand, was abundantly expressed in bronchiolar epithelial cells and airway smooth muscle cells [9,10].”
BackgroundChronic Obstructive Pulmonary Disease: Evidence for an Autoimmune Component
Stefanska, A. M., & Walsh, P. T. (2009) · Cellular and Molecular Immunology · doi:10.1038/cmi.2009.11 · Cited by 45
“Most studies in both human and animal models indicate that a Th1 type response predominates in COPD, although the presence of lung infiltrating Th2 cells has also been demonstrated indicating a degree of mechanistic heterogeneity (21, 37, 38).”
BackgroundNicola, T., Wenger, N. M., Xu, X., Evans, M. T., Qiao, L., Rezonzew, G., Yang, Y., Jilling, T., Margaroli, C., Genschmer, K. R., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51169-0 · Cited by 44
“CXCL10 isa CXCR3 ligand involved in immunomodulation; it activates T cells and is highly expressed in the small airway tissue of COPD patients 25,26 .”
Borchers, M. T., Wesselkamper, S. C., Harris, N. L., Deshmukh, H. S., Beckman, E., Vitucci, M., Tichelaar, J. W., & Leikauf, G. D. (2007) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2007.08.020 · Cited by 44
“Additionally, T cells from patients with emphysema secrete more IFNγ and IP-10 compared to control patients (7).”
BackgroundSmall Airway Mucous Metaplasia and Inflammation in Chronic Obstructive Pulmonary Disease
Kim, V., Kelemen, S. E., Abuel‐Haija, M., Gaughan, J., Sharafkaneh, A., Evans, C. M., Dickey, B. F., Solomides, C., Rogers, T. J., & Criner, G. J. (2008) · COPD Journal of Chronic Obstructive Pulmonary Disease · doi:10.1080/15412550802522445 · Cited by 44
“Some studies on COPD have reported a Th2 phenotype of lymphocytic cytokine production (20, 21), but the majority have shown a Th1 phenotype, which has not been implicated in mucous metaplasia in any study to date (22, 23).”
BackgroundRegulatory T Cells Prevent Inducible BALT Formation by Dampening Neutrophilic Inflammation
Foo, S. Y., Zhang, V., Lalwani, A., Lynch, J. P., Zhuang, A., Lam, C. E., Foster, P. S., King, C., Steptoe, R. J., Mazzone, S. B., et al. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1400909 · Cited by 43
“In addition to neutrophils, CXCR3 expression (the cognate receptor for CXCL9) is elevated on CD4 Th1 cells, on CD8 T cells, and on the B lymphocytes at the center of the follicles within iBALT (31, 41), further supporting an important role for this receptor– ligand interaction in iBALT formation and maintenance.”
BackgroundPodolin, P. L., Foley, J. P., Carpenter, D. C., Bolognese, B. J., Logan, G. A., Long, E., Harrison, O. J., & Walsh, P. T. (2013) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00152.2012 · Cited by 43
“Whereas a number of groups have previously demonstrated a positive correlation between the numbers of infiltrating CD8 cytotoxic T cells in the lungs and the degree of airflow limitation and disease progression in COPD patients (32, 37), there is increasing evidence that CD4 T helper cells may also play an important r…”
BackgroundImmune response in chronic obstructive pulmonary disease
Faner, R., Cruz, T., & Agustí, A. G. N. (2013) · Expert Review of Clinical Immunology · doi:10.1586/1744666x.2013.828875 · Cited by 43
Wohnhaas, C. T., Bassler, K. E., Watson, C. K., Shen, Y., Leparc, G., Tilp, C., Heinemann, F., Kind, D., Stierstorfer, B., Delić, D., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1325090 · Cited by 45
“Indeed, functional relevance of the N5 subset for smoke-induced lung pathology is supported by its strong expression of Cxcl10 , which is increased in sputum of COPD patients and smokers and known to induce emphysema associated MMP-12 (81, 82).”
BackgroundQin, S., Alcorn, J. F., Craigo, J. K., Tjoeng, C., Tarwater, P. M., Kolls, J. K., & Reinhart, T. A. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002876 · Cited by 42
Protective role of γδ T cells in cigarette smoke and influenza infection
Hong, M. J., Gu, B., Madison, M. C., Landers, C. T., Tung, H. Y., Kim, M.-J., Yuan, X., You, R., Machado, A. A., Gilbert, B. E., et al. (2017) · Mucosal Immunology · doi:10.1038/mi.2017.93 · Cited by 42
“…lung surface area (e.g. from normal pink to maroon color), were scored using the following ranges: 0 (pink; no evidence of discoloration), 25, 50, 75, 100% (complete maroon discoloration) 37,38 Mouse immune cell isolation from lung, draining lymph nodes, and spleen Mouse lung, draining…”
Self-citationKachuri, L., Johansson, M., Rashkin, S. R., Graff, R. E., Bossé, Y., Manem, V. S., Caporaso, N. E., Landi, M. T., Christiani, D. C., Vineis, P., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13855-2 · Cited by 44
Chemotactic Mediators of Th1 T-cell Trafficking in Smokers and COPD Patients
Brozyna, S., Ahern, J., Hodge, G. L., Nairn, J., Holmes, M., Reynolds, P. N., & Hodge, S. J. (2009) · COPD Journal of Chronic Obstructive Pulmonary Disease · doi:10.1080/15412550902724164 · Cited by 41
“Other studies that have investigated IP-10 in COPD have found increased expression compared to non-COPD patients, however these studies investigated lung sections and bronchial biopsies (13,14).”
BackgroundMethodResultInfluentialTudhope, S. J., Catley, M. C., Fenwick, P. S., Russell, R. E. K., Rumsey, W. L., Newton, R. C., Barnes, P. J., & Donnelly, L. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.9.6237 · Cited by 43
“flammation and tissue destruction in COPD (9).”
Bai, J., Qiu, S., Zhong, X.-N., Huang, Q., He, Z., Zhang, J., Liu, G., Li, M., & Deng, J. (2012) · Mediators of Inflammation · doi:10.1155/2012/410232 · Cited by 40
“mechanical fragmentation, enzymatic digestion, and centrifugation, as described in previous studies [5, 15].”
MethodSimilarities and differences in inflammatory mechanisms of asthma and COPD
Barnes, P. J. (2011) · Breathe · doi:10.1183/20734735.026410 · Cited by 42
“and express CXCR3, suggesting that they are attracted to the lungs by CXCR3-binding chemokines [44, 61].”
BackgroundLymphangiogenesis in COPD: Another link in the pathogenesis of the disease
Hardavella, G. F., Tzortzaki, E. G., Siozopoulou, V., Galanis, P., Vlachaki, E. M., Avgousti, M., Stefanou, D., & Siafakas, N. M. (2011) · Respiratory Medicine · doi:10.1016/j.rmed.2011.11.011 · Cited by 39
“It has been proposed that COPD has an autoimmune component and that LF participate in this process.(4,28,29) Up to now, there is scant information regarding the presence of lymphatics and lymphangiogenesis in the pathogenesis of chronic lung diseases, such as COPD.”
BackgroundDifferent regulation of cigarette smoke induced inflammation in upper versus lower airways
Huvenne, W., Perez-Novo, C. A., Derycke, L., Ruyck, N. D., Krysko, O., Maes, T., Pauwels, N., Robays, L. J., Bracke, K. R., Joos, G., et al. (2010) · Respiratory Research · doi:10.1186/1465-9921-11-100 · Cited by 39
“COPD is frequently considered a Th1/Tc1 disease [11], although recent developments in cytokine biology imply that COPD might be better explained by the pro-inflammatory T helper 17 (Th17) phenotype [12], * Correspondence: Wouter.”
BackgroundPinilla-Vera, M., Xiong, Z., Zhao, Y., Zhao, J., Donahoe, M. P., Barge, S., Horne, W. T., Kolls, J. K., McVerry, B. J., Birukova, A., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0159329 · Cited by 36
“However, a subset of these cells showed surface CXCR3 (Fig 1D and 1E) as previously reported [20].”
ResultFitzpatrick, M. E., Tedrow, J. R., Hillenbrand, M. E., Lucht, L. A., Richards, T. J., Norris, K. A., Zhang, Y., Sciurba, F. C., Kaminski, N., & Morris, A. (2014) · Microbiology and Immunology · doi:10.1111/1348-0421.12135 · Cited by 39
“Our data strongly suggest that colonization with Pneumocystis induces expression of CXCL3 ligands, which are known to attract effector Tcells to the lungs and also to induce alveolar macrophages to produce a metalloproteinase that is key in emphysema, MMP12 (27).”
BackgroundIL-23 Is Essential for the Development of Elastase-Induced Pulmonary Inflammation and Emphysema
Fujii, U., Miyahara, N., Taniguchi, A., Waseda, K., Morichika, D., Kurimoto, E., 古賀, 光., Kataoka, M., Gelfand, E. W., Cua, D. J., et al. (2016) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2016-0015oc · Cited by 38
Hacker, S., Lambers, C., Pollreisz, A., Höetzenecker, K., Lichtenauer, M., Mangold, A., Niederpold, T., Hacker, A., Láng, G., Dworschak, M., et al. (2009) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.20348 · Cited by 37
“Previous studies have demonstrated a predominance of TH1 cytokine milieu in COPD patients (35).”
BackgroundAirway inflammation in chronic obstructive pulmonary disease
Górska, K., Maskey‐Warzęchowska, M., & Krenke, R. (2010) · Current Opinion in Pulmonary Medicine · doi:10.1097/mcp.0b013e3283341ba0 · Cited by 37
Torvinen, M., Campwala, H., & Kilty, I. (2007) · Respiratory Research · doi:10.1186/1465-9921-8-80 · Cited by 38
“[16] Th1 cytokine phenotype has been demonstrated in peripheral blood [17] and in lung portions removed surgically from patients with COPD [18].”
BackgroundResultInfluentialPolverino, F., Mirra, D., Yang, C. X., Esposito, R., Spaziano, G., Rojas, J., Sgambato, M., Piegari, E., Cozzolino, A., Cione, E., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-26650-9 · Cited by 36
Jaques, J. A. D. S., Rezer, J. F. P., Ruchel, J. B., Gutierres, J. M., de Bairros, A. V., Farias, I. L. G., da Luz, S. C. A., Bertoncheli, C. D. M., Schetinger, M. R. C., Morsch, V. M., et al. (2010) · Analytical Biochemistry · doi:10.1016/j.ab.2010.10.039 · Cited by 38
“E-mail address: dbitencourtrosaleal@gmail.com (D 1 Abbreviations used: PMN, polymorphonuclear cell; eosinophil; COPD, chronic obstructive pulmonary dise side triphosphate diphosphohydrolase; WBC, white solution; EDTA, ethylenediaminetetraacetic acid; PBM clear cell; Pi, inorganic phosphate; TCA, trichloroacetic cell.…”
BackgroundPorter, J. C., Falzon, M., & Hall, A. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.3.1866 · Cited by 35
“The bronchial T cells associated with COPD, tuberculosis, and viral disease are of the Th1/Tc1 phenotype (10–13) and express high levels of CXCR3 (10, 13, 14).”
BackgroundAutoreactive T Cells in Human Smokers is Predictive of Clinical Outcome
Xu, C., Hesselbacher, S. E., Tsai, C., Shan, M., Spitz, M. R., Scheurer, M. E., Roberts, L., Perusich, S., Zarinkamar, N., Coxson, H. O., et al. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00267 · Cited by 35
“…neutrophils that can directly secrete elastin degrading enzymes, emphysematous lung harbors Th1 and Th17 cells that secrete cytokines and chemokines that further enhance the release of matrix metalloproteinases (Grumelli et al., 2004; Freeman et al., 2007; Kelsen et al., 2009; Shan et al., 2009).”
BackgroundInfluentialSelf-citationForsslund, H., Yang, M., Mikko, M., Karimi, R., Nyrén, S., Engvall, B., Grünewald, J., Merikallio, H., Kaarteenaho, R. L., Wahlström, J., et al. (2016) · International Journal of COPD · doi:10.2147/copd.s113625 · Cited by 35
Immune-mediated inflammation in the pathogenesis of emphysema: insights from mouse models
Craig, J. M., Scott, A. L., & Mitzner, W. (2017) · Cell and Tissue Research · doi:10.1007/s00441-016-2567-7 · Cited by 38
“In addition to these cell types, the inflammatory activity of CD4 Th1 and Th17 cells has also been associated with the progression of emphysema in human COPD (Di Stefano et al. 2009; Grumelli et al. 2004).”
Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer
Liu, Y., Lusk, C. M., Cho, M. H., Silverman, E. K., Qiao, D., Zhang, R., Scheurer, M. E., Kheradmand, F., Wheeler, D. A., Tsavachidis, S., et al. (2018) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.06.016 · Cited by 35
Self-citationDwivedi, V., Manickam, C., Binjawadagi, B., Dechamma, H. J., & Renukaradhya, G. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051794 · Cited by 35
“Frozen lung sections were immunostained as described previously [29].”
MethodRole of 5-Lipoxygenase in IL-13-Induced Pulmonary Inflammation and Remodeling
Shim, Y. M., Zhu, Z., Zheng, T., Lee, C. G., Homer, R., Ma, B., & Elias, J. A. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.3.1918 · Cited by 34
Metadata
- Authors
- Grumelli, S., Corry, D. B., Song, L.-Z., Song, L., Green, L., Huh, J., Hacken, J., Espada, R., Bag, R., Lewis, D. E., & Kheradmand, F.
- Affiliations
- Baylor College of Medicine (US)
- Michael E. DeBakey VA Medical Center (US)
- Corresponding author
- Kheradmand, Farrah
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2004-10-19
- Volume
- 1
- Issue
- 1
- Pages
- e8
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC523885
- OpenAlex
- W2108679807
- Cited by
- 484
- References
- 59
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 21 · 2023: 12 · 2022: 11 · 2021: 21 · 2020: 14 · 2019: 22 · 2018: 16 · 2017: 25 · 2016: 21 · 2015: 28 · 2014: 15 · 2013: 29 · 2012: 31
- FWCI
- 19.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Public Health Service (69585, 64061, 72419)
- National Institute of Allergy and Infectious Diseases (P30AI036211, AI 36211)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Asthma and respiratory diseases
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- chronic obstructive pulmonary disease, emphysema, Th1 cells, CXCR3, CCR5, interferon-gamma, CXCL10, macrophage metalloelastase, matrix metalloproteinase-12, elastin degradation, smoking, lung lymphocytes, chemokine receptors
- MeSH terms
- Aged, Female, Humans, Male, Middle Aged, Pulmonary Emphysema, Smoking, Tomography, X-Ray Computed, Lymphocyte Subsets, Cytokines, Macrophages, Alveolar, Th1 Cells, Disease Progression, Receptors, Chemokine, Chemokines, CXC, Pulmonary Disease, Chronic Obstructive, Chemokine CXCL10, Receptors, CXCR3
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