Pulmonary gene expression profiling of inhaled ricin

DaSilva, Luis; Cote, Dawn M.; Roy, Chad J.; Martinez, M. J.; Duniho, Steven; Pitt, M. Louise M.; Downey, Thomas J.; Dertzbaugh, Mark T.

doi:10.1016/s0041-0101(03)00035-7

Cited by 42 publications

(37 citation statements)

References 28 publications

(29 reference statements)

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“…These data are consistent with previous reports on the histopathological effects of aerosolized ricin in animal systems. 20,21,[31][32][33] In addition, we have demonstrated that instilled ricin caused widespread nuclear localization of phosphorylated ERK, p38 MAPK, and JNK, but only phosphorylated p38 MAPK was evident in control lungs. These results are consistent with data obtained by immunoblotting, which demonstrated that ricin induced a large increase in phosphorylated JNK and ERK, but not p38 MAPK (Figure 3a).…”

Section: Discussionmentioning

confidence: 69%

“…35,36 The MAPK family members are considered to be essential transducers of signals that lead to inflammatory responses. 11,[37][38][39][40] DaSilva and colleagues 33 examined a limited number (n ϭ 1176) of genes on cDNA arrays and found that 34 genes showed statistically significant changes in pulmonary gene expression after exposure of mice to inhaled ricin. Some of these transcripts were involved in tissue healing, regulation of inflammation, cell growth, apoptosis, and DNA repair.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the LD 50 of instilled ricin in C57BL6 mice in our studies was 10 g/100 g body weight, compared with aerosolized ricin in BALB/c mice of 1.4 g/100 g body weight. 33 In addition, the intrapulmonary distribution of instilled liquids occurs nonuniformly and favors the upper portions of the respiratory tract. As a result of focally high lung burdens that occur after instillation, adverse pulmonary responses may be exaggerated when compared with delivery by aerosolization.…”

Section: Discussionmentioning

confidence: 99%

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Intrapulmonary Delivery of Ricin at High Dosage Triggers a Systemic Inflammatory Response and Glomerular Damage

Wong

Korcheva

Jacoby

et al. 2007

The American Journal of Pathology

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In view of the possibility that ricin may be used as a bioweapon against human populations, we examined the pathological consequences that occur in mice after introduction of ricin into the pulmonary system. Intratracheal instillation of a lethal dose of ricin (20 g/100 g body weight) resulted in a hemorrhagic inflammatory response in multiple organs, accompanied by activation of mitogen-activated protein kinases, increased synthesis of proinflammatory RNA transcripts, and increased levels of circulating cytokines and chemokines. A sublethal dose of instilled ricin (2 g/100 g body weight) induced a similar response in lungs but did not cause detectable damage in other organs. Lungs of mice that recovered from a sublethal dose of ricin displayed evidence of fibrosis and residual damage. A lethal dose of ricin caused accumulation of proinflammatory RNA transcripts and substantial damage to 28S rRNA of multiple organs, including lung, kidney, spleen, liver, and blood, demonstrating that instilled ricin gained access to the circulation. The kidneys of mice instilled with a lethal dose of ricin showed accumulation of fibrin/fibrinogen in glomerular capillaries, increased numbers of glomerular leukocytes, and impairment of kidney function. A sublethal dose of ricin failed to induce damage to 28S rRNA in kidney or other extrapulmonary organs.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Intrapulmonary Delivery of Ricin at High Dosage Triggers a Systemic Inflammatory Response and Glomerular Damage

Wong

Korcheva

Jacoby

et al. 2007

The American Journal of Pathology

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“…For example, in rodents and nonhuman primates, the 50% lethal dose (LD 50 ) of ricin by injection is approximately 5 g/kg, while the LD 50 of ricin by inhalation is estimated to be as low as 3 g/kg (8). The respiratory mucosa is especially sensitive to ricin, as even trace amounts of toxin are known to elicit widespread necrosis in the airways and alveoli, peribronchovascular edema, mixed inflammatory cell infiltrates, and massive pulmonary alveolar flooding (9)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Chimeric Plantibody Passively Protects Mice against Aerosolized Ricin Challenge

Sully

Whaley

Bohorova

et al. 2014

Clin. Vaccine Immunol.

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e Recent incidents in the United States and abroad have heightened concerns about the use of ricin toxin as a bioterrorism agent. In this study, we produced, using a robust plant-based platform, four chimeric toxin-neutralizing monoclonal antibodies that were then evaluated for the ability to passively protect mice from a lethal-dose ricin challenge. The most effective antibody, c-PB10, was further evaluated in mice as a therapeutic following ricin exposure by injection and inhalation. Ricin toxin is a member of the medically important A-B family of plant and bacterial ribosome-inactivating proteins (RIPs) (1). In its mature form, ricin is a 65-kDa heterodimeric glycoprotein that is a natural constituent of the seeds of the castor plant (Ricinus communis). The 267-amino-acid A subunit (RTA) of ricin is an RNA N-glycosidase that depurinates a conserved adenosine residue within the so-called sarcin-ricin loop (SRL) of eukaryotic 28S rRNA, which is required for activation of the elongation factor EF-Tu (2, 3). RTA is linked via a single disulfide bond to ricin's B subunit (RTB), a 262-amino-acid lectin that is specific for glycoproteins and glycolipids terminating in galactose and Nacetylgalactosamine (Gal/GalNAc). In addition to its role in attachment, RTB also mediates the retrograde transport of ricin to the trans-Golgi network (TGN) and endoplasmic reticulum (ER), where RTA is ultimately delivered across the ER membrane and into the cytoplasm (4, 5). The extraordinary capacity of RTA to inactivate ribosomes (k cat , 1,500/min) makes ricin one of the most potent known RIPs (6, 7). For example, in rodents and nonhuman primates, the 50% lethal dose (LD 50 ) of ricin by injection is approximately 5 g/kg, while the LD 50 of ricin by inhalation is estimated to be as low as 3 g/kg (8). The respiratory mucosa is especially sensitive to ricin, as even trace amounts of toxin are known to elicit widespread necrosis in the airways and alveoli, peribronchovascular edema, mixed inflammatory cell infiltrates, and massive pulmonary alveolar flooding (9-15).The U.S. Departments of Defense (DOD) and Health and Human Services (HHS) have ongoing initiatives to develop antibody-based products capable of providing passive protection against systemic and mucosal ricin exposure (16,17). In addition to protective efficacy, issues related to platform technology, scalability, and speed of manufacturing will ultimately dictate which product(s) will be pursued for advanced development and are consistent with the unique needs for biodefense. In this regard, the Nicotiana benthamiana-based rapid antibody-manufacturing platform (RAMP) provides the potential for extremely fast and high-yield monoclonal antibody (MAb) production that has already proven to be applicable to biodefense (18-21). The technology entails mass infiltration of mature Nicotiana plants with an Agrobacterium tumefaciens suspension carrying T-DNA encoding viral replicons and results in high MAb recovery from original DNA constructs within days (22). The Nicotiana-based RAMP...

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“…In normal and malignant cells, PIM kinases are highly regulated at the transcriptional level. Expression is induced by many cellular stresses, including cytokines (13), oncogenes (14), hypoxia (15), heat shock (16), and toxin exposure (17). In addition, PIM kinases are constitutively expressed in a variety of leukemias and lymphomas (18), in head and neck squamous cell carcinomas (19), and in prostate cancer (20 -22).…”

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confidence: 99%

The PIM1 Kinase Is a Critical Component of a Survival Pathway Activated by Docetaxel and Promotes Survival of Docetaxel-treated Prostate Cancer Cells

Zemskova

Sahakian

Bashkirova

et al. 2008

Journal of Biological Chemistry

110

100

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A defining characteristic of solid tumors is the capacity to divide aggressively and disseminate under conditions of nutrient deprivation, limited oxygen availability, and exposure to cytotoxic drugs or radiation. Survival pathways are activated within tumor cells to cope with these ambient stresses. We here describe a survival pathway activated by the anti-cancer drug docetaxel in prostate cancer cells. Docetaxel activates STAT3 phosphorylation and transcriptional activity, which in turns induces expression of the PIM1 gene, encoding a serine-threonine kinase activated by many cellular stresses. Expression of PIM1 improves survival of docetaxel-treated prostate cancer cells, and PIM1 knockdown or expression of a dominant-negative PIM1 protein sensitize cells to the cytotoxic effects of docetaxel. PIM1 in turn mediates docetaxel-induced activation of NFB transcriptional activity, and PIM1 depends in part on RELA/p65 proteins for its prosurvival effects. The PIM1 kinase plays a critical role in this STAT3 3 PIM1 3 NFB stress response pathway and serves as a target for intervention to enhance the therapeutic effects of cytotoxic drugs such as docetaxel.A defining characteristic of solid tumors is the capacity to divide aggressively and metastasize under conditions of nutrient deprivation and limited oxygen availability. These microenvironmental stresses arise from inadequate perfusion as the primary tumor rapidly outgrows its initial blood supply and from dramatic structural abnormalities of tumor vessels that lead to aberrant microcirculation. Survival pathways are activated within tumor cells to cope with these ambient stresses. Examples include stress pathways that respond to hypoxia (1), oxidative stress (2), and unfolded protein/endoplasmic reticulum stresses (3). In addition to these microenvironmental stresses, anti-cancer treatment can cause additional stresses to cancer cells. These added insults call forth additional responses that can augment the survival mechanisms of the malignant cells and impair overall cell kill. Key participants in stress response pathways induced by cytotoxic drugs include AKT-and other kinase-dependent pathways (4 -8), NFB 2 pathways (9), and mediators of DNA repair (10).Among the potential survival proteins in cancer cells are the PIM family of kinases, including the PIM1, PIM2, and PIM3 genes. These small, cytoplasmic serine-threonine kinases function as true oncogenes, promoting the development of cancer in animal models, either alone (11) or synergistically with other oncogenes, such as MYC (12). In normal and malignant cells, PIM kinases are highly regulated at the transcriptional level. Expression is induced by many cellular stresses, including cytokines (13), oncogenes (14), hypoxia (15), heat shock (16), and toxin exposure (17). In addition, PIM kinases are constitutively expressed in a variety of leukemias and lymphomas (18), in head and neck squamous cell carcinomas (19), and in prostate cancer (20 -22). Therefore, PIM kinases may mediate in part the process of carcino...

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Pulmonary gene expression profiling of inhaled ricin

Cited by 42 publications

References 28 publications

Intrapulmonary Delivery of Ricin at High Dosage Triggers a Systemic Inflammatory Response and Glomerular Damage

Intrapulmonary Delivery of Ricin at High Dosage Triggers a Systemic Inflammatory Response and Glomerular Damage

Chimeric Plantibody Passively Protects Mice against Aerosolized Ricin Challenge

The PIM1 Kinase Is a Critical Component of a Survival Pathway Activated by Docetaxel and Promotes Survival of Docetaxel-treated Prostate Cancer Cells

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