Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD
Open accessAbstract
Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The independence of efferocytosis from PI3K is similar to a previous report where efferocytosis was not affected by treatment of alveolar macrophages from COPD patients with PI3K inhibitors.
“The independence of efferocytosis from PI3K is similar to a previous report where efferocytosis was not affected by treatment of alveolar macrophages from patients with chronic obstructive pulmonary disease (COPD) with PI3K inhibitors (81).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [81]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary Disease
CALVERLEY, P. M. A., Anderson, J. A., Celli, B. R., Ferguson, G. T., Jenkins, C. R., Jones, P., Yates, J., & Vestbo, J. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa063070 · Cited by 3,233 · see citing works
Fadok, V. A., Bratton, D. L., Konowal, A., Freed, P. W., Westcott, J. Y., & Henson, P. M. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1112 · Cited by 3,166 · see citing works
Susceptibility to Exacerbation in Chronic Obstructive Pulmonary Disease
Hurst, J. R., Vestbo, J., Anzueto, A. R., Locantore, N., Müllerová, H., Tal‐Singer, R., Miller, B. E., Lomas, D. A., Agustí, A. G. N., MacNee, W., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0909883 · Cited by 2,983 · see citing works
Self-citationChronic Obstructive Pulmonary Disease
Flavin, K., Morkane, C. M., & Marsh, S. (2018) · Cambridge University Press eBooks · doi:10.1017/9781108233712.025 · Cited by 2,694 · see citing works
Immunosuppressive effects of apoptotic cells
Voll, R. E., Herrmann, M., Roth, E. A., Stach, C., Kalden, J. R., & Girkontaite, I. (1997) · Nature · doi:10.1038/37022 · Cited by 1,787 · see citing works
Huynh, M.-L. N., Fadok, V., & Henson, P. (2002) · Journal of Clinical Investigation · doi:10.1172/jci11638 · Cited by 1,333 · see citing works
PI3K-Akt pathway: Its functions and alterations in human cancer
Osaki, M., Oshimura, M., & Ito, H. (2004) · APOPTOSIS · doi:10.1023/b:appt.0000045801.15585.dd · Cited by 1,266 · see citing works
Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γ in Inflammation
Hirsch, E., Katanaev, V. L., Garlanda, C., Azzolino, O., Pirola, L., Silengo, L., Sozzani, S., Mantovani, A., Altruda, F., & Wymann, M. P. (2000) · Science · doi:10.1126/science.287.5455.1049 · Cited by 1,209 · see citing works
Chronic Obstructive Pulmonary Disease
Barnes, P. J. (2000) · New England Journal of Medicine · doi:10.1056/nejm200007273430407 · Cited by 1,078 · see citing works
Self-citationDecreased histone deacetylase activity in chronic obstructive pulmonary disease.
Ito, K., Ito, M., Elliott, W., Cosío, B., Caramori, G., Kon, O. M., Barczyk, A., Hayashi, S., Adcock, I., Hogg, J. C., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa041892 · Cited by 1,043 · see citing works
Self-citationHuynh, M.-L. N., Fadok, V. A., & Henson, P. M. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0211638 · Cited by 957 · see citing works
Fukata, Y., Kaibuchi, K., Amano, M., & Kaibuchi, K. (2001) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(00)01596-0 · Cited by 748 · see citing works
Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations
Bhowmik, A. (2000) · Thorax · doi:10.1136/thorax.55.2.114 · Cited by 736 · see citing works
Patel, I. S. (2002) · Thorax · doi:10.1136/thorax.57.9.759 · Cited by 689 · see citing works
Inhaled corticosteroids for stable chronic obstructive pulmonary disease
Yang, I. A., Clarke, M., Sim, E., & Fong, K. M. (2012) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd002991.pub3 · Cited by 530 · see citing works
Crowley, M. T., Costello, P. S., Fitzer-Attas, C. J., Turner, M., Meng, F., Lowell, C., Tybulewicz, V. L. J., & DeFranco, A. L. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.186.7.1027 · Cited by 506 · see citing works
Hodge, S., Hodge, G., Scicchitano, R., Reynolds, P. N., & Holmes, M. (2003) · Immunology & Cell Biology · doi:10.1046/j.1440-1711.2003.t01-1-01170.x · Cited by 440 · see citing works
Pathogenesis of chronic obstructive pulmonary disease
Tuder, R. M., & Petrache, I. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60324 · Cited by 433 · see citing works
Toll-like receptors induce a phagocytic gene program through p38
Doyle, S. E., O'Connell, R. M., Miranda, G. A., Vaidya, S. A., Chow, E. K., Liu, P. T., Suzuki, S., Suzuki, N., Modlin, R. L., Yeh, W.-C., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20031237 · Cited by 433 · see citing works
Shaykhiev, R., Krause, A., Salit, J., Strulovici‐Barel, Y., Harvey, B., O’Connor, T. P., & Crystal, R. G. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900473 · Cited by 402 · see citing works
A Role for p38MAPK/HSP27 Pathway in Smooth Muscle Cell Migration
Hedges, J. C., Dechert, M. A., Yamboliev, I. A., Martin, J. W., Hickey, E. D., Weber, L. A., & Gerthoffer, W. T. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.34.24211 · Cited by 396 · see citing works
Defective macrophage phagocytosis of bacteria in COPD
Taylor, A. E., Finney‐Hayward, T. K., Quint, J. K., Thomas, C. M. R., Tudhope, S. J., Wedzicha, J. A., Barnes, P. J., & Donnelly, L. (2009) · European Respiratory Journal · doi:10.1183/09031936.00036709 · Cited by 358 · see citing works
Self-citationTo, Y., Ito, K., Kizawa, Y., Failla, M., Ito, M., Kusama, T., Elliott, W. M., Hogg, J. C., Adcock, I. M., & Barnes, P. J. (2010) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200906-0937oc · Cited by 356 · see citing works
Self-citationCulpitt, S. V., Rogers, D. F., Shah, P. L., de Matos, C., Russell, R. E. K., Donnelly, L., & Barnes, P. J. (2002) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200204-298oc · Cited by 333 · see citing works
Self-citationRho-Kinase–Mediated Contraction of Isolated Stress Fibers
Katoh, K., Kano, Y., Amano, M., Onishi, H., Kaibuchi, K., & Fujiwara, K. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.3.569 · Cited by 331 · see citing works
Both Erk and p38 Kinases Are Necessary for Cytokine Gene Transcription
Carter, A. B., Monick, M. M., & Hunninghake, G. W. (1999) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.20.4.3420 · Cited by 305 · see citing works
New Concepts in Chronic Obstructive Pulmonary Disease
Barnes, P. J. (2003) · Annual Review of Medicine · doi:10.1146/annurev.med.54.101601.152209 · Cited by 290 · see citing works
Self-citationThe Stress-Induced MAP Kinase p38 Regulates Endocytic Trafficking via the GDI:Rab5 Complex
Cavalli, V., Vilbois, F., Felberbaum‐Corti, M., Marcote, M. J., Tamura, K., Karin, M., Arkinstall, S., & Gruenberg, J. E. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00189-7 · Cited by 288 · see citing works
Dynamin 2 Is Required for Phagocytosis in Macrophages
Gold, E. S., Underhill, D. M., Morrissette, N. S., Guo, J., McNiven, M. A., & Aderem, A. A. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.12.1849 · Cited by 286 · see citing works
A contractile activity that closes phagosomes in macrophages
Swanson, J. A., Johnson, M. T., Beningo, K. A., Post, P. L., Mooseker, M. S., & Araki, N. (1999) · Journal of Cell Science · doi:10.1242/jcs.112.3.307 · Cited by 282 · see citing works
Exacerbations of Chronic Obstructive Pulmonary Disease
Desai, H., & Sethi, S. (2016) · CRC Press eBooks · doi:10.3109/9781420080353-7 · Cited by 270 · see citing works
Increased activation of p38 MAPK in COPD
Renda, T., Baraldo, S., Pelaia, G., Bazzan, E., Turato, G., Papi, A. A., Maestrelli, P., Maselli, R., Vatrella, A., Fabbri, L. M., et al. (2007) · European Respiratory Journal · doi:10.1183/09031936.00036707 · Cited by 257 · see citing works
Activation of RhoA and ROCK Are Essential for Detachment of Migrating Leukocytes
Alblas, J., Ulfman, L. H., Hordijk, P. L., & Koenderman, L. (2001) · Molecular Biology of the Cell · doi:10.1091/mbc.12.7.2137 · Cited by 256 · see citing works
Rho-Kinase and Myosin-II Control Phagocytic Cup Formation during CR, but Not FcγR, Phagocytosis
Olazabal, I. M., Caron, E., May, R. C., Schilling, K., Knecht, D. A., & Machesky, L. M. (2002) · Current Biology · doi:10.1016/s0960-9822(02)01069-2 · Cited by 237 · see citing works
Berenson, C. S., Garlipp, M. A., Grove, L., Maloney, J., & Sethi, S. (2006) · The Journal of Infectious Diseases · doi:10.1086/508428 · Cited by 213 · see citing works
Araki, N., Hatae, T., Furukawa, A., & Swanson, J. A. (2002) · Journal of Cell Science · doi:10.1242/jcs.00235 · Cited by 190 · see citing works
Novel Rho Kinase Inhibitors with Anti-inflammatory and Vasodilatory Activities
Doe, C. P., Bentley, R. G., Behm, D. J., Lafferty, R., Stavenger, R. A., Jung, D. K., Bamford, M. J., Panchal, T. A., Grygielko, E. T., Wright, L. L., et al. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.110635 · Cited by 159 · see citing works
PI3K accelerates, but is not required for, neutrophil chemotaxis to fMLP
Heit, B., Liu, L., Colarusso, P., Puri, K. D., & Kubes, P. (2008) · Journal of Cell Science · doi:10.1242/jcs.020412 · Cited by 156 · see citing works
Cigarette Smoke Impairs Clearance of Apoptotic Cells through Oxidant-dependent Activation of RhoA
Richens, T. R., Linderman, D. J., Horstmann, S. A., Lambert, C. L., Xiao, Y., Keith, R. L., Boé, D. M., Morimoto, K., Bowler, R. P., Day, B. J., et al. (2009) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200807-1148oc · Cited by 153 · see citing works
Engulfment of Apoptotic Cells Is Negatively Regulated by Rho-mediated Signaling
Tosello‐Trampont, A., Nakada‐Tsukui, K., & Ravichandran, K. S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306079200 · Cited by 153 · see citing works
Gordon, S. B., Irving, G. R. B., Lawson, R. A., Lee, M. E., & Read, R. C. (2000) · Infection and Immunity · doi:10.1128/iai.68.4.2286-2293.2000 · Cited by 140 · see citing works
MacNee, W., Allan, R., Jones, I., Salvo, M. C. D., & Tan, L. F. (2013) · Thorax · doi:10.1136/thoraxjnl-2012-202744 · Cited by 139 · see citing works
Dockrell, D. H., Lee, M., Lynch, D. H., & Read, R. C. (2001) · The Journal of Infectious Diseases · doi:10.1086/323084 · Cited by 131 · see citing works
Self-citationNavas, T. A., Mohindru, M., Estes, M. L., Jing, Y., Sokol, L., Pahanish, P., Parmar, S., Haghnazari, E., Zhou, L., Collins, R. H., et al. (2006) · Blood · doi:10.1182/blood-2006-05-023093 · Cited by 127 · see citing works
Dockrell, D. H., Whyte, M. K. B., & Mitchell, T. J. (2012) · CHEST Journal · doi:10.1378/chest.12-0210 · Cited by 125 · see citing works
Self-citationMarriott, H. M., Ali, F., Read, R. C., Mitchell, T. J., Whyte, M. K. B., & Dockrell, D. H. (2004) · The FASEB Journal · doi:10.1096/fj.03-1450fje · Cited by 119 · see citing works
Self-citationImpaired macrophage phagocytosis of bacteria in severe asthma
Liang, Z., Zhang, Q., Thomas, C. M. R., Chana, K. K., Gibeon, D. S., Barnes, P. J., Chung, K. F., Bhavsar, P. K., & Donnelly, L. (2014) · Respiratory Research · doi:10.1186/1465-9921-15-72 · Cited by 115 · see citing works
Self-citationLomas, D. A., Lipson, D. A., Miller, B. E., Willits, L. R., Keene, O. N., Barnacle, H., Barnes, N. C., & Tal‐Singer, R. (2011) · The Journal of Clinical Pharmacology · doi:10.1177/0091270010397050 · Cited by 112 · see citing works
McLeish, K. R., Klein, J. B., Coxon, P. Y., Head, K. Z., & Ward, R. A. (1998) · Journal of Leukocyte Biology · doi:10.1002/jlb.64.6.835 · Cited by 110 · see citing works
Singh, D., Smyth, L. J. C., Borrill, Z., Sweeney, L. M., & Tal‐Singer, R. (2009) · The Journal of Clinical Pharmacology · doi:10.1177/0091270009347873 · Cited by 108 · see citing works
Self-citationCurrent Controversies and Future Perspectives in Chronic Obstructive Pulmonary Disease
Agustí, A. G. N., & Vestbo, J. (2011) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201103-0405pp · Cited by 108 · see citing works
Doukas, J., Eide, L., Stebbins, K. J., Racanelli‐Layton, A. L., Dellamary, L. A., Martin, M., Dneprovskaia, E., Noronha, G., Söll, R., Wrasidlo, W., et al. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.144311 · Cited by 104 · see citing works
Smith, S. J., Fenwick, P. S., Nicholson, A. G., Kirschenbaum, F., Finney‐Hayward, T. K., Higgins, L. S., Giembycz, M. A., Barnes, P. J., & Donnelly, L. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706885 · Cited by 103 · see citing works
Self-citationRequirement for PI 3-kinase γ in macrophage migration to MCP-1 and CSF-1
Jones, G. E., Prigmore, E., Calvez, R., Hogan, C., Dunn, G., Hirsch, E., Wymann, M. P., & Ridley, A. J. (2003) · Experimental Cell Research · doi:10.1016/s0014-4827(03)00318-5 · Cited by 103 · see citing works
Exacerbations of chronic obstructive pulmonary disease
Kidney, J. (2002) · Thorax · doi:10.1136/thorax.57.9.753 · Cited by 102 · see citing works
Marriott, H. M., Bingle, C. D., Read, R. C., Braley, K. E., Kroemer, G., Hellewell, P. G., Craig, R. W., Whyte, M. K. B., & Dockrell, D. H. (2005) · Journal of Clinical Investigation · doi:10.1172/jci200521766 · Cited by 100 · see citing works
Self-citationProtein Kinases as Small Molecule Inhibitor Targets in Inflammation
Gaestel, M., Mengel, A., Bothe, U., & Asadullah, K. (2007) · Current Medicinal Chemistry · doi:10.2174/092986707781696636 · Cited by 96 · see citing works
Ali, F., Lee, M. E., Iannelli, F., Pozzi, G., Mitchell, T. J., Read, R. C., & Dockrell, D. H. (2003) · The Journal of Infectious Diseases · doi:10.1086/378675 · Cited by 93 · see citing works
Self-citationThe Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor
Duffy, J. P., Harrington, E. M., Salituro, F. G., Cochran, J. E., Green, J., Gao, H., Bemis, G. W., Evindar, G., Galullo, V., Ford, P. J., et al. (2011) · ACS Medicinal Chemistry Letters · doi:10.1021/ml2001455 · Cited by 91 · see citing works
Moretto, N., Bertolini, S., Iadicicco, C., Marchini, G., Kaur, M., Volpi, G., Patacchini, R., Singh, D., & Facchinetti, F. (2012) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00046.2012 · Cited by 90 · see citing works
Self-citationMarriott, H. M., Bingle, C. D., Read, R. C., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci21766 · Cited by 89 · see citing works
Li, X., Udagawa, N., Takami, M., Sato, N., Kobayashi, Y., & Takahashi, N. (2003) · Endocrinology · doi:10.1210/en.2003-0166 · Cited by 85 · see citing works
Armstrong, J., Harbron, C. G., Lea, S., Booth, G. C., Cadden, P., WREGGETT, K. A., & Singh, D. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.180737 · Cited by 84 · see citing works
Self-citationReactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia
Marriott, H. M., Jackson, L. E., Wilkinson, T. S., Simpson, A. J., Mitchell, T. J., Buttle, D. J., Cross, S. S., Ince, P. G., Hellewell, P. G., Whyte, M. K. B., et al. (2008) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200707-990oc · Cited by 82 · see citing works
Self-citationImportance of Phosphoinositide 3-Kinase γ in the Host Defense against Pneumococcal Infection
Maus, U. A., Backi, M., Winter, C., Srivastava, M., Schwarz, M. K., Rückle, T., Paton, J. C., Briles, D. E., Mack, M., Welte, T., et al. (2007) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200610-1533oc · Cited by 73 · see citing works
Tudhope, S. J., Finney‐Hayward, T. K., Nicholson, A. G., Mayer, R. J., Barnette, M. S., Barnes, P. J., & Donnelly, L. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.127670 · Cited by 67 · see citing works
Self-citationArmstrong, J., Sargent, C. A., & Singh, D. (2009) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2009.03986.x · Cited by 67 · see citing works
Self-citationHenry, P. J., Mann, T. S., & Goldie, R. G. (2004) · Pulmonary Pharmacology & Therapeutics · doi:10.1016/j.pupt.2004.10.002 · Cited by 66 · see citing works
p38 MAPK-Dependent Phagocytic Encapsulation Confers Infection Tolerance in Drosophila
Shinzawa, N., Nelson, B., Aonuma, H., Okado, K., Fukumoto, S., Miura, M., & Kanuka, H. (2009) · Cell Host & Microbe · doi:10.1016/j.chom.2009.07.010 · Cited by 62 · see citing works
Barnes, P. J., & Kleinert, S. (2004) · The Lancet · doi:10.1016/s0140-6736(04)16866-9 · Cited by 62 · see citing works
Self-citationMatsumura, F., Totsukawa, G., Yamakita, Y., & Yamashiro, S. (2001) · Cell Structure and Function · doi:10.1247/csf.26.639 · Cited by 62 · see citing works
Chopra, P., Kanoje, V., Semwal, A., & Ray, A. (2008) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.17.10.1411 · Cited by 61 · see citing works
Bogaert, D., van der Valk, P., Ramdin, R., Sluijter, M., Monninkhof, E. M., Hendrix, R., de Groot, R., & Hermans, P. W. M. (2004) · Infection and Immunity · doi:10.1128/iai.72.2.818-823.2004 · Cited by 59 · see citing works
A Rap/Phosphatidylinositol 3-Kinase Pathway Controls Pseudopod Formation
Kortholt, A., Bolourani, P., Rehmann, H., Keizer‐Gunnink, I., Weeks, G., Wittinghofer, A., & Haastert, P. J. M. V. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e09-03-0177 · Cited by 55 · see citing works
Boé, D. M., Richens, T. R., Horstmann, S. A., Burnham, E. L., Janssen, W. J., Henson, P. M., Moss, M. M., & Vandivier, R. W. (2010) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2010.01259.x · Cited by 55 · see citing works
Allen, L. H., Allgood, J. A., Han, X., & Wittine, L. M. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.0205091 · Cited by 47 · see citing works
Tamura, N., Hazeki, K., Okazaki, N., Kametani, Y., Murakami, H., Takaba, Y., Ishikawa, Y., Nigorikawa, K., & Hazeki, O. (2009) · Biochemical Journal · doi:10.1042/bj20090687 · Cited by 47 · see citing works
Phagocytosis of Wild-TypeLegionella pneumophilaOccurs through a Wortmannin-Insensitive Pathway
Khelef, N., Shuman, H. A., & Maxfield, F. R. (2001) · Infection and Immunity · doi:10.1128/iai.69.8.5157-5161.2001 · Cited by 46 · see citing works
Forsberg, M., Blomgran, R., Lerm, M., Särndahl, E., Sebti, S. M., Hamilton, A. D., Stendahl, O. I., & Zheng, L. (2003) · Journal of Leukocyte Biology · doi:10.1189/jlb.1202586 · Cited by 45 · see citing works
Development of New Drugs for COPD
Barnes, P. J. (2013) · Current Medicinal Chemistry · doi:10.2174/0929867311320120005 · Cited by 40 · see citing works
Self-citationInhaled corticosteroids for stable chronic obstructive pulmonary disease
Yang, I. A., Fong, K. M., & Black, P. (2001) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd002991 · Cited by 37 · see citing works
Shiratsuchi, H., & Basson, M. D. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00543.2004 · Cited by 35 · see citing works
Mai, P., Tian, L., Yang, L., Wang, L., Yang, L., & Li, L. (2014) · Journal of Cellular Physiology · doi:10.1002/jcp.24911 · Cited by 33 · see citing works
Duong‐Quy, S., Dao, P., Hua-Huy, T., Guilluy, C., Pacaud, P., & Dinh‐Xuan, A. T. (2010) · European Respiratory Journal · doi:10.1183/09031936.00056610 · Cited by 31 · see citing works
Hällgren, O., Enes, S. R., Andersson‐Sjöland, A., Nihlberg, K., Wieslander, E., Reimer, M. K., Dahlbäck, M., Eriksson, L. T., Bjermer, L. H., Erjefalt, J. S., et al. (2012) · Journal of Translational Medicine · doi:10.1186/1479-5876-10-171 · Cited by 31 · see citing works
Millan, D. S. (2011) · Future Medicinal Chemistry · doi:10.4155/fmc.11.96 · Cited by 24 · see citing works
Phosphoinositides in Chemotaxis
Weiger, M. C., & Parent, C. A. (2012) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-007-3015-1_7 · Cited by 23 · see citing works
Quan, H. Y., Kim, J., Lee, H., Lee, S., Choi, J. I., & Bae, H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0127885 · Cited by 22 · see citing works
Kinase Targets and Inhibitors for the Treatment of Airway Inflammatory Diseases
Adcock, I. M., & Caramori, G. (2004) · BioDrugs · doi:10.2165/00063030-200418030-00003 · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ritchie, A. I., & Wedzicha, J. A. (2020) · Clinics in Chest Medicine · doi:10.1016/j.ccm.2020.06.007 · Cited by 403 · see citing works
Self-citationMacLeod, M. A., Papi, A. A., Contoli, M., Beghé, B., Celli, B. R., Wedzicha, J. A., & Fabbri, L. M. (2021) · Respirology · doi:10.1111/resp.14041 · Cited by 377 · see citing works
Self-citationUnderstanding the role of neutrophils in chronic inflammatory airway disease
Jasper, A. E., McIver, W. J., Sapey, E., & Walton, G. (2019) · F1000Research · doi:10.12688/f1000research.18411.1 · Cited by 189 · see citing works
Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly
De Maeyer, R. P. H., van de Merwe, R. C., Louie, R., Bracken, O. V., Devine, O. P., Goldstein, D. R., Uddin, M., Akbar, A. N., & Gilroy, D. W. (2020) · Nature Immunology · doi:10.1038/s41590-020-0646-0 · Cited by 182 · see citing works
Lung Macrophage Phenotypes and Functional Responses: Role in the Pathogenesis of COPD
Yamasaki, K., & van Eeden, S. V. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020582 · Cited by 127 · see citing works
Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages
Belchamber, K. B. R., Singh, R., Batista, C., Whyte, M. K. B., Dockrell, D. H., Kilty, I., Robinson, M. J., Wedzicha, J. A., Barnes, P. J., & Donnelly, L. (2019) · European Respiratory Journal · doi:10.1183/13993003.02244-2018 · Cited by 138 · see citing works
Self-citationMetabolomics and transcriptomics pathway approach reveals outcome-specific perturbations in COPD
Cruickshank-Quinn, C. I., Jacobson, S. R., Hughes, G. J., Powell, R. L., Petrache, I., Kechris, K. J., Bowler, R. P., & Reisdorph, N. A. (2018) · Scientific Reports · doi:10.1038/s41598-018-35372-w · Cited by 98 · see citing works
Ryan, E. M., Sadiku, P., Coelho, P., Watts, E., Zhang, A., Howden, A. J. M., Sánchez-García, M. A., Bewley, M. A., Cole, J., McHugh, B. J., et al. (2023) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202203-0482oc · Cited by 94 · see citing works
Self-citationBowdish, D. M. E. (2018) · CHEST Journal · doi:10.1016/j.chest.2018.09.003 · Cited by 85 · see citing works
Dysregulated Functions of Lung Macrophage Populations in COPD
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 85 · see citing works
Implications of the Immune Landscape in COPD and Lung Cancer: Smoking Versus Other Causes
Taucher, E., Mykoliuk, I., Lindenmann, J., & Smolle-Jüettner, F.-M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.846605 · Cited by 79 · see citing works
de Groot, L. E. S., van der Veen, A., Martínez, F. O., Hamann, J., Lutter, R., & Melgert, B. N. (2018) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00456.2018 · Cited by 76 · see citing works
Neutrophilic Inflammation in the Pathogenesis of Chronic Obstructive Pulmonary Disease
Butler, A., Walton, G., & Sapey, E. (2018) · COPD Journal of Chronic Obstructive Pulmonary Disease · doi:10.1080/15412555.2018.1476475 · Cited by 73 · see citing works
Finney, L., Belchamber, K. B. R., Fenwick, P. S., Kemp, S. V., Edwards, M. R., Mallia, P., Donaldson, G. C., Johnston, S. L., Donnelly, L., & Wedzicha, J. A. (2018) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201806-1095oc · Cited by 69 · see citing works
Self-citationGalectin-3 enhances monocyte-derived macrophage efferocytosis of apoptotic granulocytes in asthma
Erriah, M., Pabreja, K., Fricker, M., Baines, K. J., Donnelly, L., Bylund, J., Karlsson, A., & Simpson, J. L. (2019) · Respiratory Research · doi:10.1186/s12931-018-0967-9 · Cited by 68 · see citing works
Self-citationAcute respiratory distress syndrome is associated with impaired alveolar macrophage efferocytosis
Mahida, R. Y., Scott, A., Parekh, D., Lugg, S. T., Hardy, R., Lavery, G. G., Matthay, M. A., Naidu, B. V., Perkins, G. D., & THICKETT, D. R. (2021) · European Respiratory Journal · doi:10.1183/13993003.00829-2021 · Cited by 67 · see citing works
Guan, R., Wang, J., Li, Z., Ding, M., Li, D., Xu, G., Wang, T., Chen, Y., Yang, Q., Long, Z., et al. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00263 · Cited by 66 · see citing works
p38 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 56 · see citing works
Macrophage phagocytosis cracking the defect code in COPD
Jubrail, J., Kurian, N., & Niedergang, F. (2017) · Biomedical Journal · doi:10.1016/j.bj.2017.09.004 · Cited by 54 · see citing works
New drugs under development for COPD
Uwagboe, I., Adcock, I. M., Bello, F. L., Caramori, G., & Mumby, S. E. (2022) · Minerva Medica · doi:10.23736/s0026-4806.22.08024-7 · Cited by 53 · see citing works
Progression of the PI3K/Akt signaling pathway in chronic obstructive pulmonary disease
Liu, Y., Kong, H., Cai, H., Chen, G., Chen, H., & Ruan, W. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1238782 · Cited by 54 · see citing works
Building toolkits for COPD exacerbations: lessons from the past and present
Sapey, E., Bafadhel, M., Bolton, C. E., Wilkinson, T. M. A., Hurst, J. R., & Quint, J. K. (2019) · Thorax · doi:10.1136/thoraxjnl-2018-213035 · Cited by 50 · see citing works
Macrophage Polarization and Functions in Pathogenesis of Chronic Obstructive Pulmonary Disease
Kim, G.-D., Lim, E. Y., & Shin, H. S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115631 · Cited by 54 · see citing works
Zhang, P., Xin, X., Fang, L., Jiang, H., Xu, X., Su, X., & Shi, Y. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.10.007 · Cited by 44 · see citing works
Zhang, X., Ding, M., Cheng, C., Zhang, Y., Xiang, S.-Y., Lu, J., & Liu, Z.-B. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106230 · Cited by 43 · see citing works
Microbiome Modulation as a Novel Strategy to Treat and Prevent Respiratory Infections
Mindt, B. C., & DiGiandomenico, A. (2022) · Antibiotics · doi:10.3390/antibiotics11040474 · Cited by 44 · see citing works
PI3K signalling in chronic obstructive pulmonary disease and opportunities for therapy
Moradi, S., Jarrahi, E., Ahmadi, A., Salimian, J., Karimi, M., Zarei, A., Jamalkandi, S. A., & Ghanei, M. (2021) · The Journal of Pathology · doi:10.1002/path.5696 · Cited by 39 · see citing works
Inhaled RNA Therapeutics for Obstructive Airway Diseases: Recent Advances and Future Prospects
Xu, Y., Thakur, A., Zhang, Y., & Foged, C. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13020177 · Cited by 38 · see citing works
Targeting defective pulmonary innate immunity – A new therapeutic option?
Belchamber, K. B. R., & Donnelly, L. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107500 · Cited by 37 · see citing works
Self-citationFaniyi, A. A., Hughes, M., Scott, A., Belchamber, K. B. R., & Sapey, E. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15759 · Cited by 32 · see citing works
Self-citationROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension
Montagnoli, T. L., da Silva, J. S., Sudo, S. Z., Santos, A. D., Gomide, G. F., de Sá, M. P. L., & Zapata‐Sudo, G. (2021) · Cells · doi:10.3390/cells10071648 · Cited by 31 · see citing works
Fine particulate matter inhibits phagocytosis of macrophages by disturbing autophagy
Li, Y., Yong, Y., Yang, M., Wang, W., Qu, X., Dang, X., Shang, D., Shao, Y., Liu, J., & Chang, Y. (2020) · The FASEB Journal · doi:10.1096/fj.202000657r · Cited by 29 · see citing works
ROCK Inhibition Drives Resolution of Acute Inflammation by Enhancing Neutrophil Apoptosis
Galvão, I., Athayde, R. M., Perez, D., Reis, A. C., Rezende, L., de Oliveira, V. L. S., Rezende, B. M., Gonçalves, W. A., Sousa, L. P., Teixeira, M. M., et al. (2019) · Cells · doi:10.3390/cells8090964 · Cited by 28 · see citing works
Mitogen-Activated Protein Kinases (MAPKs) and Enteric Bacterial Pathogens: A Complex Interplay
Nandi, I., & Aroeti, B. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241511905 · Cited by 26 · see citing works
Phosphoinositide 3-kinase δ (PI3Kδ) in respiratory disease
Stokes, C. A., & Condliffe, A. M. (2018) · Biochemical Society Transactions · doi:10.1042/bst20170467 · Cited by 25 · see citing works
Kharbili, M. E., Aviszus, K., Sasse, S. K., Zhao, X., Serban, K. A., Majka, S. M., Gerber, A. N., & Gally, F. (2022) · The FASEB Journal · doi:10.1096/fj.202200128r · Cited by 24 · see citing works
New drugs under development for COPD
Bello, F. L., Hansbro, P. M., Donovan, C., Coppolino, I., Mumby, S. E., Adcock, I. M., & Caramori, G. (2020) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2020.1819982 · Cited by 23 · see citing works
Macrophages and the microbiome in chronic obstructive pulmonary disease
Sandhu, K. K., Scott, A., Tatler, A. L., Belchamber, K. B. R., & Cox, M. J. (2024) · European Respiratory Review · doi:10.1183/16000617.0053-2024 · Cited by 21 · see citing works
Self-citationDysregulated Neutrophil Phenotype and Function in Hospitalised Non-ICU COVID-19 Pneumonia
Belchamber, K. B. R., Thein, O. S., Hazeldine, J., Grudzinska, F. S., Faniyi, A. A., Hughes, M., Jasper, A. E., Yip, K. P., Crowley, L., Lugg, S. T., et al. (2022) · Cells · doi:10.3390/cells11182901 · Cited by 20 · see citing works
Self-citationEfferocytosis and Respiratory Disease
Zheng, W., Zhou, Z., Guo, X., Zuo, X., Zhang, J., An, Y., Zheng, H., Yue, Y., Wang, G., & Wang, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914871 · Cited by 17 · see citing works
Zhang, S., Zhu, L., Dai, H., & Pan, L. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.108208 · Cited by 16 · see citing works
Leukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy
Baker, J. R., & Donnelly, L. (2021) · International Journal of COPD · doi:10.2147/copd.s266394 · Cited by 16 · see citing works
Self-citationLimax extract ameliorates cigarette smoke-induced chronic obstructive pulmonary disease in mice
Liang, X., Wang, J., Guan, R., Zhao, L., Li, D., Long, Z., Yang, Q., Xu, J., Wang, Z., Xie, J.-K., et al. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.11.004 · Cited by 15 · see citing works
Tang, F., Ling, C., & Liu, J. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.04.091 · Cited by 13 · see citing works
Lea, S., Gaskell, R., Hall, S., Maschera, B., Hessel, E. M., & Singh, D. (2021) · Clinical & Experimental Immunology · doi:10.1111/cei.13638 · Cited by 13 · see citing works
Self-citationKruckow, K. L., Murray, E., Shayhidin, E., Rosenberg, A. F., Bowdish, D. M. E., & Orihuela, C. J. (2024) · Aging Cell · doi:10.1111/acel.14133 · Cited by 11 · see citing works
Lu, R., Xu, K., Qin, Y., Shao, X., Yan, M., Liao, Y., Wang, B., Zhao, J., Li, J., & Tian, Y. (2022) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2022/4838650 · Cited by 10 · see citing works
Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells
Bendre, S. V., Wang, Y., Hajyousif, B., K C, R., Bhogale, S. G., Pradeep, D., Krawczynska, N., Schane, C. P., Weisser, E., Singh, A., et al. (2026) · Science Advances · doi:10.1126/sciadv.adx5490 · Cited by 8 · see citing works
Darlyuk‐Saadon, I., Heng, C. K. M., Bai, C. G., Gilad, N., Yu, W., Mok, M. M. H., Wong, W. S. F., & Engelberg, D. (2021) · FEBS Journal · doi:10.1111/febs.15697 · Cited by 8 · see citing works
Mahida, R. Y., Scott, A., Parekh, D., Lugg, S. T., Belchamber, K. B. R., Hardy, R., Matthay, M. A., Naidu, B. V., & THICKETT, D. R. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.737859 · Cited by 8 · see citing works
Self-citationCazzola, M., Page, C. P., Rogliani, P., Calzetta, L., & Matera, M. G. (2025) · Drugs · doi:10.1007/s40265-025-02179-9 · Cited by 6 · see citing works
Lewicki, S., Bałan, B. J., Stelmasiak, M., Radomska-Leśniewska, D. M., Szymański, Ł., Rios-Turek, N., Bień, J., Szarpak, Ł., & Hajduk, B. (2025) · Vaccines · doi:10.3390/vaccines13020107 · Cited by 3 · see citing works
Chen, K., Zhang, M., Fan, L., & Wang, Z. (2022) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2022/8823231 · Cited by 2 · see citing works
Atay, E., Altan, A., Yetkin, D., & Ayaz, F. (2025) · Food Science & Nutrition · doi:10.1002/fsn3.70622 · Cited by 1 · see citing works
COPD Biologics: Right Patient, Right Pathway, Right Time
Finney, L., Conway, F. M., & Sethi, D. (2026) · Pulmonary Therapy · doi:10.1007/s41030-026-00370-1 · Cited by 1 · see citing works
(2024) · Frontiers research topics · doi:10.3389/978-2-8325-4643-7 · Cited by 1 · see citing works
Yamaguchi, A., Ma, X., Uemura, M., Tanida, K., Nishimura, N., Tan, J., Nakagami, G., Sanada, H., Su, D., Sarosiek, K. A., et al. (2025) · The FASEB Journal · doi:10.1096/fj.202501797r · Cited by 2 · see citing works
Romanelli, A. M., Raciti, M., Papa, A., & Prediletto, R. (2022) · Journal of Biomedical Research & Environmental Sciences · doi:10.37871/jbres1615 · Cited by 1 · see citing works
Bacterial Colonization in COPD
Donnelly, L. (2021) · Elsevier eBooks · doi:10.1016/b978-0-08-102723-3.00242-0
Self-citationHeller, N. M. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.734764469.793567816
Bowden, K. A., Wright, C., Clark, S. J., Correa, T. F., Johnston, S. A., Marriott, H. M., Francis, S., & Prince, L. R. (2026) · Journal of Inflammation · doi:10.1186/s12950-026-00495-9
From clinical phenotypes to cellular mechanisms: a precision medicine framework for COPD
Wu, J., Cheng, X., Yu, F., Wang, R., Zhao, B., Zhao, H., Zhang, W., & Chen, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1846920
Parasitic infections as immunomodulatory modifiers of chronic obstructive pulmonary disease
Grumelli, S. (2026) · International Journal of Immunopathology and Pharmacology · doi:10.1177/03946320261490459
Uncoupling lens EMT: Blocking p38 MAPK suppresses TGF-β-driven myofibroblast transdifferentiation
Wu, Y., Flokis, M., Soghomonian, S., & Lovicu, F. J. (2026) · Experimental Eye Research · doi:10.1016/j.exer.2026.111290
- Authors
- Bewley, M. A., Belchamber, K. B. R., Chana, K. K., Budd, R. C., Donaldson, G., Wedzicha, J. A., Brightling, C. E., Kilty, I., Donnelly, L. E., Barnes, P. J., Singh, D., Whyte, M. K. B., Dockrell, D. H., & COPDMAP
- Affiliations
- University of Sheffield (GB)
- Imperial College London (GB)
- Manchester Academic Health Science Centre (GB)
- University of Leicester (GB)
- Pfizer (United States) (US)
- Centre for Inflammation Research (GB)
- Sheffield Teaching Hospitals NHS Foundation Trust (GB)
- Corresponding author
- Bewley, Martin A.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-09-28
- Volume
- 11
- Issue
- 9
- Pages
- e0163139
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5040258
- OpenAlex
- W2527008720
- Cited by
- 64
- References
- 88
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 8 · 2021: 12 · 2020: 6 · 2019: 6 · 2018: 10 · 2017: 3
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- Pfizer
- GlaxoSmithKline (G1001367/1)
- Royal Brompton and Harefield NHS Foundation Trust (G1001367/1)
- National Institute for Health and Care Research (NF-SI-0510-10270, G1001367/1, RP-PG-0109-10056, NF-SI-0513-10077, NF-SI-0611-10148)
- University of Leicester
- Imperial College London (G1001367/1)
- Medical Research Council (G1001367/1)
- Innovate UK
- NIHR Sheffield Clinical Research Facility
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Keywords
- chronic obstructive pulmonary disease, macrophage phagocytosis, efferocytosis, apoptotic neutrophils, p38 MAPK inhibitor, PI3K inhibitors, ROCK inhibitor, alveolar macrophages, monocyte-derived macrophages, Streptococcus pneumoniae, Haemophilus influenzae, intracellular bacterial killing
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
