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Dive into the research topics where John C. Gomez is active.

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Featured researches published by John C. Gomez.


American Journal of Respiratory Cell and Molecular Biology | 2015

Mechanisms of Interferon-γ Production by Neutrophils and Its Function during Streptococcus pneumoniae Pneumonia

John C. Gomez; Mitsuhiro Yamada; Jessica R. Martin; Hong Dang; W. June Brickey; Wolfgang Bergmeier; Mary C. Dinauer; Claire M. Doerschuk

Bacterial pneumonia is a common public health problem associated with significant mortality, morbidity, and cost. Neutrophils are usually the earliest leukocytes to respond to bacteria in the lungs. Neutrophils rapidly sequester in the pulmonary microvasculature and migrate into the lung parenchyma and alveolar spaces, where they perform numerous effector functions for host defense. Previous studies showed that migrated neutrophils produce IFN-γ early during pneumonia induced by Streptococcus pneumoniae and that early production of IFN-γ regulates bacterial clearance. IFN-γ production by neutrophils requires Rac2, Hck/Lyn/Fgr Src family tyrosine kinases, and NADPH oxidase. Our current studies examined the mechanisms that regulate IFN-γ production by lung neutrophils during acute S. pneumoniae pneumonia in mice and its function. We demonstrate that IFN-γ production by neutrophils is a tightly regulated process that does not require IL-12. The adaptor molecule MyD88 is critical for IFN-γ production by neutrophils. The guanine nucleotide exchange factor CalDAG-GEFI modulates IFN-γ production. The CD11/CD18 complex, CD44, Toll-like receptors 2 and 4, TRIF, and Nrf2 are not required for IFN-γ production by neutrophils. The recently described neutrophil-dendritic cell hybrid cell, identified by its expression of Ly6G and CD11c, is present at low numbers in pneumonic lungs and is not a source of IFN-γ. IFN-γ produced by neutrophils early during acute S. pneumoniae pneumonia induces transcription of target genes in the lungs, which are critical for host defense. These studies underline the complexity of the neutrophil responses during pneumonia in the acute inflammatory response and in subsequent resolution or initiation of immune responses.


American Journal of Pathology | 2008

The Role of Rac2 in Regulating Neutrophil Production in the Bone Marrow and Circulating Neutrophil Counts

John C. Gomez; Jindrich Soltys; Keiichi Okano; Mary C. Dinauer; Claire M. Doerschuk

Circulating neutrophils are persistently higher in mice deficient in the small GTPase Rac2 than in wild-type (WT) mice. Therefore, we examined the mechanisms through which the small GTPase Rac2 regulates neutrophil production and release. Lethally irradiated WT mice reconstituted with a 50:50 mixture of WT and Rac2(-/-) fetal liver cells were protected from neutrophilia, suggesting that neutrophilia is primarily because of extrinsic defects that can be corrected by WT leukocytes. However, the differential counts and numbers of leukocyte subtypes differed between Rac2(-/-) and WT cells, suggesting that Rac2 modulates leukocyte lineage distribution. Kinetic studies suggest Rac2 modulates the release of neutrophils into the circulation and does not prolong their circulating half life. The percentage of bone marrow cells that expressed the neutrophil marker Gr-1 in lethally irradiated WT or Rac2(-/-) recipients of Rac2(-/-) stem cells was greater than in recipients of WT stem cells; however, circulating neutrophil counts were higher only in Rac2(-/-) recipients of Rac2(-/-) stem cells. Rac2 mRNA was expressed in the bone marrow of WT recipients of Rac2(-/-) stem cells and in human mesenchymal stem cells. The data presented here suggest that Rac2 in hematopoietic cells regulates leukocyte lineage distribution and Rac2 in nonhematopoietic cells might contribute to regulating circulating neutrophil counts.


American Journal of Physiology-lung Cellular and Molecular Physiology | 2017

Biomarkers of exposure to new and emerging tobacco delivery products

Suzaynn F. Schick; Benjamin C. Blount; Peyton Jacob; Najat Saliba; John T. Bernert; Ahmad El Hellani; Peter Jatlow; R. Steven Pappas; Lanqing Wang; Jonathan Foulds; Arunava Ghosh; Stephen S. Hecht; John C. Gomez; Jessica R. Martin; Clementina Mesaros; Sanjay Srivastava; Gideon St.Helen; Robert Tarran; Pawel Lorkiewicz; Ian A. Blair; Heather L. Kimmel; Claire M. Doerschuk; Neal L. Benowitz; Aruni Bhatnagar

Accurate and reliable measurements of exposure to tobacco products are essential for identifying and confirming patterns of tobacco product use and for assessing their potential biological effects in both human populations and experimental systems. Due to the introduction of new tobacco-derived products and the development of novel ways to modify and use conventional tobacco products, precise and specific assessments of exposure to tobacco are now more important than ever. Biomarkers that were developed and validated to measure exposure to cigarettes are being evaluated to assess their use for measuring exposure to these new products. Here, we review current methods for measuring exposure to new and emerging tobacco products, such as electronic cigarettes, little cigars, water pipes, and cigarillos. Rigorously validated biomarkers specific to these new products have not yet been identified. Here, we discuss the strengths and limitations of current approaches, including whether they provide reliable exposure estimates for new and emerging products. We provide specific guidance for choosing practical and economical biomarkers for different study designs and experimental conditions. Our goal is to help both new and experienced investigators measure exposure to tobacco products accurately and avoid common experimental errors. With the identification of the capacity gaps in biomarker research on new and emerging tobacco products, we hope to provide researchers, policymakers, and funding agencies with a clear action plan for conducting and promoting research on the patterns of use and health effects of these products.


Laboratory Investigation | 2010

The role of CD18 in the production and release of neutrophils from the bone marrow

John C. Gomez; Claire M. Doerschuk

Neutrophil numbers must be tightly controlled to maintain host protection and prevent neutrophil-mediated tissue injury. CD18 deficiency leads to neutrophilia and myeloid hyperplasia in the bone marrow (BM). These studies examined the function of CD18 in regulating neutrophil production and determined whether the defects in neutrophil production that are observed in CD18 deficiency persist in the presence of wild-type (WT) leukocytes that confer host protection. Neutrophil production was evaluated in CD18−/− mice and lethally irradiated WT mice reconstituted with mixtures of CD18−/− and WT stem cells. Neutrophil kinetic studies suggest that CD18 may facilitate the release of the most mature neutrophils into the circulation. The proportion of CD18−/− neutrophils in chimeric animals was greater than the proportion of CD18−/− donor cells used to reconstitute the mice, and the percentage of CD18−/− leukocytes that were neutrophils was greater than for WT leukocytes, indicating that CD18 may regulate the lineage distribution of hematopoietic cells in the blood and BM. The proportion of Annexin V+ Gr-1+ cells in both the BM of chimeric animals and in vitro cultures of WT and CD18−/− hematopoietic stem cells was lower in CD18−/− than in WT cells, suggesting that CD18 modulates apoptosis. These data suggest that CD18 directly regulates neutrophil production, in part by limiting the survival of neutrophils and their precursors. Thus, the granulocytosis observed in CD18−/− mice and CD18-deficient patients is due to both defects in host defense and BM-intrinsic functions of CD18 in regulating neutrophil production.


Journal of Immunology | 2016

Nrf2 modulates host defense during streptococcus pneumoniae pneumonia in mice

John C. Gomez; Hong Dang; Jessica R. Martin; Claire M. Doerschuk

Nrf2 regulates the transcriptional response to oxidative stress. These studies tested the role of Nrf2 during Streptococcus pneumoniae pneumonia and identified Nrf2-dependent genes and pathways in lung tissue and in recruited neutrophils. Nrf2 null and wild type (WT) mice were studied at 6 and 24 h after instillation of S. pneumoniae or PBS. At 6 h, fewer neutrophils were recruited and the number of bacteria remaining in the lungs tended to be less (p = 0.06) in the Nrf2 null compared with WT mice. In uninfected lungs, 53 genes were already differentially expressed in Nrf2 null compared with WT mouse lungs, and gene sets involved in phagocytosis, Fc receptor function, complement, and Ig regulation are enhanced in PBS-treated Nrf2 null gene profiles compared with those of WT mice. These results suggest that initial host defense is enhanced in Nrf2 null mice, resulting in less recruitment of neutrophils. At 24 h, neutrophil recruitment was greater. The percentages of early apoptotic and late apoptotic/necrotic neutrophils were similar. At increasing inoculum numbers, mortality rates strikingly increased from 15 to 31 and 100% in Nrf2 null mice, whereas all WT mice survived, and Nrf2 null mice had a defect in clearance, particularly at the intermediate dose. The mortality was due to enhanced lung injury and greater systemic response. Gene profiling identified differentially regulated genes and pathways in neutrophils and lung tissue, including those involved in redox stress response, metabolism, inflammation, immunoregulatory pathways, and tissue repair, providing insight into the mechanisms for the greater tissue damage and increased neutrophil accumulation.


Scientific Reports | 2017

Predicted effects of observed changes in the mRNA and microRNA transcriptome of lung neutrophils during S. pneumoniae pneumonia in mice

John C. Gomez; Hong Dang; Matthew Kanke; Robert S. Hagan; Jason R. Mock; Samir N. Kelada; Praveen Sethupathy; Claire M. Doerschuk

The complex role of neutrophils in modulating the inflammatory response is increasingly appreciated. Our studies profiled the expression of mRNAs and microRNAs (miRs) in lung neutrophils in mice during S. pneumoniae pneumonia and performed in depth in silico analyses. Lung neutrophils were isolated 24 hours after intratracheal instillation of PBS or S. pneumoniae, and differentially expressed (DE) mRNAs and miRs were identified. Lung neutrophils from mice with S. pneumoniae pneumonia contained 4127 DE mRNAs, 36% of which were upregulated at least 2-fold. During pneumonia, lung neutrophils increase expression of pattern recognition receptors, receptors for inflammatory mediators, transcription factors including NF-κB and AP-1, Nrf2 targets, cytokines, chemokines and other inflammatory mediators. Interestingly, neutrophils responded to Type I interferons, whereas they both produced and responded to Type II interferon. Expression of regulators of the inflammatory and immune response was verified at the mRNA and protein level. Of approximately 1100 miRs queried, 31 increased and 67 decreased more than 2-fold in neutrophils from S. pneumoniae pneumonia. Network analyses of potential DE miR-target DE mRNA interactions revealed candidate key regulatory miRs. Thus, S. pneumoniae modulates mRNA and miR expression by lung neutrophils, increasing their ability to respond and facilitating host defense.


American Journal of Respiratory Cell and Molecular Biology | 2017

Activating integrins isn't always "beta" for neutrophil migration!

John C. Gomez; Claire M. Doerschuk

The lungs possess extraordinary defenses against bacteria and other stimuli. Initial mechanisms of host defense include the very effective mucociliary escalator and the alveolarmacrophages, which clear many stimuli without inducing an inflammatory response and recruitment of circulating leukocytes. When these defenses are overwhelmed, epithelial cells and macrophages call in help from outside the lungs. In response to bacteria, neutrophils are usually first to arrive, and their response is quick, recognizing a need within minutes. Neutrophil adhesion and migration within the pulmonary microvasculature are unique in important ways. Neutrophil emigration into the distal lung occurs primarily through the capillary bed, rather than the postcapillary venules, where the paradigm of leukocyte rolling followed by firm adhesion and migration was developed (1, 2). The pulmonary capillaries have a complex geometry of branching segments, and the diameter of at least half the segments is narrower than a spherical neutrophil so that rolling cannot occur (3–6). Although the leukocyte adhesion complex CD11/CD18 is not always required for neutrophil emigration in the lungs, Pseudomonas aeruginosa induces CD11/CD18-dependent neutrophil recruitment (6–8). CD18 is the b2-integrin subunit mediating both outside-in signaling after binding of a ligand and inside-out signaling that results in activation of the adhesion complex through a two-step process (9–11). Clustering of integrins induced by ligand binding can initiate association of two cytosolic proteins, talin-1 and kindlin-3, with two distinct sites on the short cytoplasmic tail of CD18. Considerable data suggest that talin-1 initiates the conformational change in all b-integrins from a compact/bent state to an extended closed headpiece (intermediate binding affinity), whereas kindlin-3 is required for transformation of this intermediate state to an extended open headpiece state with a high binding affinity for ligands (9, 10). In this issue of the Journal, Wilson and colleagues (pp. 620–627) elegantly ask critical questions about the requirements for talin-1 and kindlin-3 in neutrophil migration during P. aeruginosa–induced pneumonia (12). In striking contrast to studies showing that these molecules are required for neutrophil transmigration into the peritoneum (11), talin-1 is not required for neutrophil recruitment into the lungs. Moreover, kindlin-3–null neutrophils migrate in greater numbers than wild-type neutrophils, suggesting that kindlin-3–null neutrophils have an advantage. Importantly, antibody blockade shows that CD18 is still required for emigration of kindlin-3–null neutrophils. Studies to determine the site within the lungs where neutrophils enter more abundantly to account for this advantage show that the neutrophils lacking either talin-1 or kindlin-3 have no defect in sequestering within the lung capillaries, but do have an advantage in migrating into the interstitium compared with wild-type neutrophils, suggesting that activated integrins may slow neutrophil transit through the interstitium (12). The mutant neutrophils’ advantage does not further increase as they migrate from the interstitium into the lavageable airspace. Walker and colleagues (2, 13, 14) suggest that the path neutrophils take is through the endothelial junctions on the thick side of the capillaries, fully accumulating within the interstitium, and then migrating between type I and type II alveolar epithelial cells into the alveolar space. Taken together, activated integrins appear to slow neutrophil migration through the interstitium, but have less impact on migration through the alveolar epithelium. An alternative explanation, that activated integrins slow neutrophil migration through the epithelium and result in a “backup” in the interstitium, seems unlikely. These studies are elegantly performed using mice, the bone marrow of which has been reconstituted with a mixture of mutant and wild-type bone marrow, allowing comparison of each genotype within the same mouse. The radiation dose (10 Gy) does induce a lung injury, including replacement of alveolar macrophages with bone marrow–derived cells and an immune cell infiltrate within the bronchovascular bundle, but an impact of this on the results seems unlikely. These studies have the technical caveats that flushing the vasculature does not completely differentiate between the circulating and sequestering neutrophils, and that bronchoalveolar lavage does not remove all the neutrophils that have emigrated into the alveoli. One does wonder whether neutrophils that cannot transform their integrins into a high activation state might be less sticky and more lavageable than wildtype neutrophils, but the major process that activated integrins appear to be impeding is trafficking through the interstitium. Furthermore, these studies address the effect of a b2-integrin allosteric antagonist, XVA143, that mimics the deficiency of kindlin-3 by preventing the transformation from mid to high affinity (12). Importantly, XVA143 also results in greater numbers of neutrophils in the interstitium and the bronchoalveolar lavage fluid. This twoto threefold increase in neutrophils does not increase lung injury, as measured by wet-to-dry weights, or alter bacterial clearance. Studies using immortalized myeloid progenitors differentiated toward a neutrophil phenotype show that generation of reactive oxygen species in response to P. aeruginosa is not altered by deficiency of either talin-1 or kindlin-3, but phagocytosis is reduced by about half. Why this defect in phagocytosis does not result in less clearance of bacteria from the lungs is not clear, but perhaps sufficient numbers of neutrophils are recruited to overcome this defect. Whether XVA143 has therapeutic use as an enhancer of neutrophil recruitment, perhaps during antibiotic-resistant infections, remains to be determined.


Archive | 2013

Neutrophils in Acute Bacterial Pneumonia

John C. Gomez; Qin Wang; Claire M. Doerschuk

During bacterial pneumonias, neutrophils are usually the first leukocytes recruited from the circulation to the lung, where they protect the host by killing microbial pathogens through phagocytosis and the release of antimicrobial products. In addition to their role in eliminating pathogens, the role of neutrophils in shaping the immune response and resolution of inflammation is now increasingly appreciated. Patients with defects in neutrophil production or function suffer from recurrent microbial infections, thus illustrating the critical role of neutrophils in host defense. However, the very characteristics and functions that make neutrophils useful to the host can also injure host tissues, and neutrophil-mediated tissue damage has been implicated in the pathogenesis of a number of serious disorders, including ALI and ARDS, in which both these beneficial and harmful effects are integrated.


Investigative Ophthalmology & Visual Science | 2002

Regulation of Endotoxin-Induced Keratitis by PECAM-1, MIP-2, and Toll-like Receptor 4

Saloni Khatri; Jonathan H. Lass; Fred P. Heinzel; W. Matthew Petroll; John C. Gomez; Eugenia Diaconu; Carolyn M. Kalsow; Eric Pearlman


American Journal of Respiratory and Critical Care Medicine | 2011

Interferon-γ Production by Neutrophils during Bacterial Pneumonia in Mice

Mitsuhiro Yamada; John C. Gomez; Pauline E. Chugh; Clifford A. Lowell; Mary C. Dinauer; Dirk P. Dittmer; Claire M. Doerschuk

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Claire M. Doerschuk

University of North Carolina at Chapel Hill

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Hong Dang

University of North Carolina at Chapel Hill

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Jessica R. Martin

University of North Carolina at Chapel Hill

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Mitsuhiro Yamada

University of North Carolina at Chapel Hill

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Mary C. Dinauer

Washington University in St. Louis

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Arunava Ghosh

University of North Carolina at Chapel Hill

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Benjamin C. Blount

Centers for Disease Control and Prevention

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Carolyn M. Kalsow

Case Western Reserve University

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