The Journal of Clinical Investigation

Our medical research library holds 10 studies published in The Journal of Clinical Investigation (1987–2022). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 10 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: American Society for Clinical Investigation
• Published: 1924 to the present, United States
• Language: English
• ISSN: 0021-9738 (print), 1558-8238 (electronic)
• Its record in the NLM Catalog

2020s

• Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma. D. Chen, S.B. Le, T.E. Hutchinson, et al. 2022;132(8). PubMed · Publisher · Free full text

  Abstract

  Tumor Treating Fields (TTFields), an approved therapy for glioblastoma (GBM) and malignant mesothelioma, employ noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to disrupt the mitotic spindle, leading to chromosome missegregation and apoptosis. Emerging evidence suggests that TTFields may also induce inflammation. However, the mechanism underlying this property and whether it can be harnessed therapeutically are unclear. Here, we report that TTFields induced focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that intensely recruited and activated 2 major DNA sensors - cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2) - and their cognate cGAS/stimulator of interferon genes (STING) and AIM2/caspase 1 inflammasomes to produce proinflammatory cytokines, type 1 interferons (T1IFNs), and T1IFN-responsive genes. In syngeneic murine GBM models, TTFields-treated GBM cells induced antitumor memory immunity and a cure rate of 42% to 66% in a STING- and AIM2-dependent manner. Using single-cell and bulk RNA sequencing of peripheral blood mononuclear cells, we detected robust post-TTFields activation of adaptive immunity in patients with GBM via a T1IFN-based trajectory and identified a gene panel signature of TTFields effects on T cell activation and clonal expansion. Collectively, these studies defined a therapeutic strategy using TTFields as cancer immunotherapy in GBM and potentially other solid tumors.

2010s

• A dual role for the immune response in a mouse model of inflammation-associated lung cancer. M. Dougan, D. Li, D. Neuberg, et al. 2011;121(6):2436-46. PubMed · Publisher · Free full text

  Abstract

  Lung cancer is the leading cause of cancer death worldwide. Both principal factors known to cause lung cancer, cigarette smoke and asbestos, induce pulmonary inflammation, and pulmonary inflammation has recently been implicated in several murine models of lung cancer. To further investigate the role of inflammation in the development of lung cancer, we generated mice with combined loss of IFN-γ and the β-common cytokines GM-CSF and IL-3. These immunodeficient mice develop chronic pulmonary inflammation and lung tumors at a high frequency. Examination of the relationship between these tumors and their inflammatory microenvironment revealed a dual role for the immune system in tumor development. The inflammatory cytokine IL-6 promoted optimal tumor growth, yet wild-type mice rejected transplanted tumors through the induction of adaptive immunity. These findings suggest a model whereby cytokine deficiency leads to oncogenic inflammation that combines with defective antitumor immunity to promote lung tumor formation, representing a unique system for studying the role of the immune system in lung tumor development.

1990s

• Asbestos inhalation induces reactive nitrogen species and nitrotyrosine formation in the lungs and pleura of the rat. S. Tanaka, N. Choe, D.R. Hemenway, et al. 1998;102(2):445-54. PubMed · Publisher · Free full text

  Abstract

  To determine whether asbestos inhalation induces the formation of reactive nitrogen species, three groups of rats were exposed intermittently over 2 wk to either filtered room air (sham-exposed) or to chrysotile or crocidolite asbestos fibers. The rats were killed at 1 or 6 wk after exposure. At 1 wk, significantly greater numbers of alveolar and pleural macrophages from asbestos-exposed rats than from sham-exposed rats demonstrated inducible nitric oxide synthase protein immunoreactivity. Alveolar macrophages from asbestos-exposed rats also generated significantly greater nitrite formation than did macrophages from sham-exposed rats. Strong immunoreactivity for nitrotyrosine, a marker of peroxynitrite formation, was evident in lungs from chrysotile- and crocidolite-exposed rats at 1 and 6 wk. Staining was most evident at alveolar duct bifurcations and within bronchiolar epithelium, alveolar macrophages, and the visceral and parietal pleural mesothelium. Lungs from sham-exposed rats demonstrated minimal immunoreactivity for nitrotyrosine. Significantly greater quantities of nitrotyrosine were detected by ELISA in lung extracts from asbestos-exposed rats than from sham-exposed rats. These findings suggest that asbestos inhalation can induce inducible nitric oxide synthase activation and peroxynitrite formation in vivo, and provide evidence of a possible alternative mechanism of asbestos-induced injury to that thought to be induced by Fenton reactions.

• Asbestos induces apoptosis of human and rabbit pleural mesothelial cells via reactive oxygen species. V.C. Broaddus, L. Yang, L.M. Scavo, et al. 1996;98(9):2050-9. PubMed · Publisher · Free full text

  Abstract

  Mesothelial cells, the progenitor cell of the asbestos-induced tumor mesothelioma, are particularly sensitive to the toxic effects of asbestos, although the molecular mechanisms by which asbestos induces injury in mesothelial cells are not known. We asked whether asbestos induced apoptosis in mesothelial cells and whether reactive oxygen species were important. Pleural mesothelial cells (rabbit or human) were exposed to asbestos (crocidolite, amosite, or chrysotile) or control particles at moderate doses (1-10 microg/cm2) over 24 h and evaluated for oligonucleosomal DNA fragmentation, loss of membrane phospholipid asymmetry, and nuclear condensation. Asbestos fibers, not control particles, induced apoptosis in mesothelial cells by all assays and induction of apoptosis was dose dependent for all types of asbestos, with crocidolite (5 microg/cm2) inducing 15.0+/-1.1% (mean+/-SE; n = 12) apoptosis versus control particles < 4%. Apoptosis induced by asbestos, but not by actinomycin D, was inhibited by extracellular catalase, superoxide dismutase in the presence of catalase, hypoxia (8% oxygen), deferoxamine, 3-aminobenzamide [an inhibitor of poly(ADP-ribosyl) polymerase], and cytochalasin B. Only catalase and cytochalasin B decreased fiber uptake. We conclude that asbestos induces apoptosis in mesothelial cells via reactive oxygen species. Escape from this pathway could allow the abnormal survival of mesothelial cells with asbestos-induced mutations.

• Vitronectin enhances internalization of crocidolite asbestos by rabbit pleural mesothelial cells via the integrin alpha v beta 5. A.M. Boylan, D.A. Sanan, D. Sheppard, et al. 1995;96(4):1987-2001. PubMed · Publisher · Free full text

  Abstract

  The mechanism by which pleural mesothelial cells, the likely progenitor cells of asbestos-induced mesothelioma, recognize and internalize crocidolite asbestos is unknown. Because incubation of asbestos fibers with serum increases their association with cells, we asked whether a protein coat on asbestos increased internalization of fibers via specific cellular receptors. Coating crocidolite with citronectin, but not with fibronectin or other proteins, increased fiber internalization by rabbit pleural mesothelial cells, as measured by a new technique using fluorescence confocal microscopy. Receptors for vitronectin, alpha v beta 3 and alpha v beta 5, were identified on mesothelial cells. Inhibiting vitronectin receptors by plating cells on a vitronectin substrate or incubating cells with excess soluble vitronectin reduced internalization of vitronectin-coated crocidolite. Inhibition of alpha v beta 5, but not alpha v beta 3, with blocking antibodies similarly reduced internalization. In addition, alpha v beta 5, but not alpha v beta 3, showed immunocytochemical colocalization with fibers. Of biologic relevance, coating crocidolite with serum also increased internalization via alpha v beta 5, an effect dependent on the vitronectin in serum. We conclude that pleural mesothelial cells recognize and internalize vitronectin- and serum-coated asbestos via the integrin alpha v beta 5. Since integrins initiate some of the same signaling pathways as does asbestos, our findings may provide insights into the mechanisms of asbestos-induced biologic effects.

• Chrysotile asbestos upregulates gene expression and production of alpha-receptors for platelet-derived growth factor (PDGF-AA) on rat lung fibroblasts. J.C. Bonner, A.L. Goodell, P.G. Coin, et al. 1993;92(1):425-30. PubMed · Publisher · Free full text

  Abstract

  PDGF isoforms have been postulated to serve as mediators of fibroblast proliferation and chemotaxis during lung fibrogenesis induced by asbestos inhalation. We have studied the interaction of chrysotile asbestos fibers with rat lung fibroblasts (RLF) in vitro and the consequent changes in PDGF receptor mRNA expression, PDGF binding, and mitogenic activity of PDGF isoforms. Northern blot analysis revealed that mRNA for the PDGF-receptor alpha subtype (PDGF-R alpha) on RLF was upregulated after a 24-h exposure to asbestos in culture (0.5-15 micrograms fibers/cm2). [125I]PDGF-BB receptor assays showed that normal RLF possess mainly PDGF-R beta and a paucity of PDGF-R alpha. In agreement with the Northern data, saturation binding of [125I]PDGF-BB to RLF exposed to asbestos demonstrated an approximately 40% increase in binding sites accompanied by a twofold decrease in receptor affinity. Treating asbestos-exposed RLF with PDGF-AA, which binds only PDGF-R alpha, blocked the PDGF binding sites that were upregulated by fiber exposure. PDGF-AA had increased mitogenic potency for fiber-exposed RLF, but PDGF-BB was a less potent mitogen for these RLF. Nonfibrogenic carbonyl iron spheres induced similar changes in PDGF growth responses. These data show that inorganic particulates alter the PDGF-R alpha population on RLF without significant change in PDGF-R beta.

• Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-alpha-dependent mechanism in murine macrophages. P.W. Noble, F.R. Lake, P.M. Henson, et al. 1993;91(6):2368-77. PubMed · Publisher · Free full text

  Abstract

  Macrophages participate in inflammatory and repair processes in part through the selective release of cytokines that contribute to tissue remodeling. Extracellular matrix components generated at inflammatory sites may influence tissue remodeling by effects on leukocyte adherence and local cytokine production. In murine bone marrow-derived macrophages, we found that soluble hyaluronic acid stimulated IL-1 beta, TNF alpha, and insulin-like growth factor-1 (IGF-1) mRNA transcript expression as well as IGF-1 protein synthesis. Monoclonal antibodies to the hyaluronic acid receptor CD44 blocked the effects of hyaluronic acid on IL-1 beta, TNF alpha, and IGF-1 expression. TNF alpha and IL-1 beta mRNA expression preceded IGF-1 protein synthesis, and TNF alpha, but not IL-1 beta, was found to directly stimulate IGF-1. Furthermore, IGF-1 induction was dependent on endogenous TNF alpha production since IGF-1 protein synthesis was inhibited in the presence of anti-TNF alpha antiserum. In addition, IL-1 beta was found to exert a regulatory role on IGF-1 production by enhancing the TNF alpha effect. IL-1 beta and TNF alpha mRNA transcript expression as well as IGF-1 protein synthesis were also stimulated by chrysotile asbestos. Anti-CD44 antibodies had no effect whereas anti-TNF alpha antiserum blocked asbestos-stimulated IGF-1 production. These results indicate that hyaluronate activation of CD44 induces cytokine expression and macrophage-derived IGF-1 production is dependent on TNF alpha expression.

• Restrictive lung function and asbestos-induced pleural fibrosis. A quantitative approach. D.A. Schwartz, J.R. Galvin, S.J. Yagla, et al. 1993;91(6):2685-92. PubMed · Publisher · Free full text

  Abstract

  To assess further the clinical significance of asbestos-induced pleural fibrosis, we used a computer algorithm to reconstruct images three dimensionally from the high-resolution computerized tomography (HRCT) scan of the chest in 60 asbestos-exposed subjects. Pulmonary function tests, chest radiographs, and HRCT scans were performed on all study subjects. The volume of asbestos-induced pleural fibrosis was computed from the three-dimensional reconstruction of the HRCT scan. Among those with pleural fibrosis identified on the HRCT scan (n = 29), the volume of the pleural lesion varied from 0.01% (0.5 ml) and 7.11% (260.4 ml) of the total chest cavity. To investigate the relationship between asbestos-induced pleural fibrosis and restrictive lung function, we compared the computer-derived estimate of pleural fibrosis to the total lung capacity and found that these measures were inversely related (r = -0.40; P = 0.002). After controlling for age, height, pack-years of cigarette smoking, and the presence of interstitial fibrosis on the chest radiograph, the volume of pleural fibrosis identified on the three-dimensional reconstructed image from the HRCT scan was inversely associated with the total lung capacity (P = 0.03) and independently accounted for 9.5% of the variance of this measure of lung volume. These findings further extend the scientific data supporting an independent association between pleural fibrosis and restrictive lung function.

• Evidence of a role for mesothelial cell-derived interleukin 8 in the pathogenesis of asbestos-induced pleurisy in rabbits. A.M. Boylan, C. Rüegg, K.J. Kim, et al. 1992;89(4):1257-67. PubMed · Publisher · Free full text

  Abstract

  Although acute asbestos-induced pleurisy is characterized by an influx of neutrophils, the identity of the factors that attract these cells to the pleural space and the source of the factors are unknown. We found that instillation of crocidolite asbestos into the pleural space of rabbits led to the appearance in pleural liquid of chemotactic activity for neutrophils, and that this chemotactic activity was inhibited significantly by a neutralizing antibody to human interleukin 8 (IL-8). Cultured rabbit pleural mesothelial cells incubated with crocidolite asbestos also released chemotactic activity for neutrophils, which was inhibited significantly by the anti-IL-8 antibody. To determine whether rabbit pleural mesothelial cells synthesize IL-8, we generated a probe for rabbit IL-8 mRNA by amplifying cDNA prepared from stimulated pleural mesothelial cells using the polymerase chain reaction (PCR) and primers based on homologous sequences in human and sheep IL-8 cDNAs. Homology-based PCR yielded a single cDNA fragment with a nucleotide sequence 88% identical to that of a corresponding region of human IL-8 cDNA. With the radiolabeled PCR product as a probe, we demonstrated rapid induction of IL-8 mRNA expression in pleural mesothelial cells exposed to asbestos. As expected, tumor necrosis factor-alpha also led to the appearance of IL-8 in the rabbit pleural space and stimulated cultured pleural mesothelial cells to synthesize and release IL-8. We conclude that asbestos directly stimulates pleural mesothelial cells to synthesize IL-8 and that mesothelial cell-derived IL-8 may play an important role in mediating asbestos-induced pleural inflammation.

1980s

• Role of oxidants in DNA damage. Hydroxyl radical mediates the synergistic DNA damaging effects of asbestos and cigarette smoke. J.H. Jackson, I.U. Schraufstatter, P.A. Hyslop, et al. 1987;80(4):1090-5. PubMed · Publisher · Free full text

  Abstract

  The mechanism by which cigarette smoking and asbestos exposure synergistically increase the incidence of lung cancer is unknown. We hypothesized that cigarette smoke and asbestos might synergistically increase DNA damage. To test this hypothesis we exposed isolated bacteriophage PM2 DNA to cigarette smoke and/or asbestos, and assessed DNA strand breaks as an index of DNA damage. Our results supported our hypothesis. 78 +/- 12% of the DNA exposed to both cigarette smoke and asbestos developed strand breaks, while only 9.8 +/- 7.0 or 4.3 +/- 3.3% of the DNA exposed to cigarette smoke or asbestos, respectively, developed strand breaks under the conditions of the experiment. Our experimental evidence suggested that cigarette smoke and asbestos synergistically increased DNA damage by stimulating .OH formation. First, significant amounts of .OH were detected by electron paramagnetic resonance (EPR) in DNA mixtures containing both cigarette smoke and asbestos, but no .OH was detected in mixtures containing cigarette smoke alone or asbestos alone. Second, the .OH scavengers, dimethylsulfoxide (DMSO), mannitol, or Na benzoate decreased both .OH detection by EPR and strand breaks in DNA mixtures exposed to cigarette smoke and asbestos. Third, the H2O2 scavenger, catalase, and the iron chelators, 1,10-phenanthroline and desferrithiocin, decreased both .OH detection and strand breaks in DNA mixtures exposed to cigarette smoke and asbestos. These latter findings suggest that iron contained in asbestos may catalyze the formation of .OH from H2O2 generated by cigarette smoke. In summary, our study indicates that cigarette smoke and asbestos synergistically increase DNA damage and suggests that this synergism may involve .OH production.

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