Murine Respiratory Mycoplasmosis, Rat and Mouse

Schoeb, Trenton R.; Davis, J. K.; Lindsey, J. Russell

doi:10.1007/978-3-642-61042-4_11

Cited by 16 publications

(27 citation statements)

References 34 publications

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“…Previously, we examined vascular remodeling in C3H mice, which are unusually susceptible to M. pulmonis infection and have particularly severe vascular changes (1). M. pulmonis is a naturally occurring pathogen that commonly infects and remodels the respiratory tract of rodents housed under "conventional" nonbarrier conditions (31)(32)(33). Endothelial cell division, as shown by BrdU labeling, peaks in C3H mice at 5 days of infection (8), demonstrating that the capillary enlargement occurs by endothelial cell division and is not simply vasodilatation.…”

Section: Discussionmentioning

confidence: 99%

TNF-α drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice

Bałuk¹,

Yao²,

Feng³

et al. 2009

J. Clin. Invest.

165

180

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Inflammation is associated with blood vessel and lymphatic vessel proliferation and remodeling. The microvasculature of the mouse trachea provides an ideal opportunity to study this process, as Mycoplasma pulmonis infection of mouse airways induces widespread and sustained vessel remodeling, including enlargement of capillaries into venules and lymphangiogenesis. Although the mediators responsible for these vascular changes in mice have not been identified, VEGF-A is known not to be involved. Here, we sought to determine whether TNF-α drives the changes in blood vessels and lymphatics in M. pulmonis-infected mice. The endothelial cells, but not pericytes, of blood vessels, but not lymphatics, were immunoreactive for TNF receptor 1 (TNF-R1) and lymphotoxin B receptors. Most TNF-R2 immunoreactivity was on leukocytes. Infection resulted in a large and sustained increase in TNF-α expression, as measured by real-time quantitative RT-PCR, and smaller increases in lymphotoxins and TNF receptors that preceded vessel remodeling. Substantially less vessel remodeling and lymphangiogenesis occurred when TNF-α signaling was inhibited by a blocking antibody or was silenced in Tnfr1 -/-mice. When administered after infection was established, the TNF-α-specific antibody slowed but did not reverse blood vessel remodeling and lymphangiogenesis. The action of TNF-α on blood vessels is probably mediated through direct effects on endothelial cells, but its effects on lymphangiogenesis may require inflammatory mediators from recruited leukocytes. We conclude that TNF-α is a strong candidate for a mediator that drives blood vessel remodeling and lymphangiogenesis in inflammation. IntroductionA wide spectrum of changes in blood vessels occurs in inflammation. Acute inflammation is accompanied by reversible vasodilatation, increased blood flow, plasma extravasation, and leukocyte adhesion and transmigration. In chronic inflammation, characteristic of asthma, obstructive pulmonary disease, rheumatoid arthritis, psoriasis, and inflammatory bowel disease, blood vessels and lymphatic vessels proliferate and undergo remodeling with changes in structural, functional, and molecular phenotypes. As part of the remodeling, capillaries enlarge and transform into venules that contribute to leukocyte adhesion and migration unpublished observations). Lymphatic vessels not only sprout and proliferate but also enlarge and undergo phenotypic changes (4, 5).Although much attention has been devoted to sprouting angiogenesis in cancer, less is known about the factors that govern vascular remodeling in inflammation. The microvasculature of the mouse trachea presents an opportunity to study such factors because it (a) has a regular segmented 2D architecture repeated between and over the tracheal cartilage rings; (b) can be subjected to short-and long-lasting inflammatory stimuli (6); and (c) is a site of angiogenesis, vascular remodeling, and lymphangiogenesis after infection by Mycoplasma pulmonis. A conspicuous early feature of vascular remodeling in the ...

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Section: Discussionmentioning

confidence: 99%

TNF-α drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice

Bałuk¹,

Yao²,

Feng³

et al. 2009

J. Clin. Invest.

165

180

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“…19,31,35,46 We consider that the weight of available evidence favors the hypothesis that lesions of M. pulmonis disease were interpreted as lymphoma in the aspartame, MTBE, and methanol bioassays, as this would account for the reported occurrence of lympho-immunoblastic lymphoma in the lung, whereas spontaneous tumors of immunoblastic type are rare in Sprague-Dawley rats, and the organ distribution and cellular morphology are uncharacteristic of immunoblastic or other wellcharacterized types of lymphoma in rats. Such interpretation of lesions of M. pulmonis disease also could account for reported dose-related increases in lymphoma occurrence, due to exacerbation of M. pulmonis disease by the test chemical, which is consistent with known features of the disease.…”

Section: Summary and Discussionmentioning

confidence: 98%

Mycoplasma pulmonis and Lymphoma in Bioassays in Rats

et al. 2009

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Abstract. Lymphomas were reported to be induced in rats in bioassays of aspartame, methyltertiary-butyl ether (MTBE), and other chemicals conducted by a nonprofit cancer research organization. European regulatory authorities concluded that lymphomas in the aspartame study were caused by Mycoplasma pulmonis and suggested that this also was the case for the MTBE bioassay. To assess the role of M. pulmonis in these bioassays, we reviewed the tumor data for the aspartame and MTBE bioassays and, additionally, the organization's bioassay of methanol. For all 3 studies, the most frequently reported hematopoietic neoplasm was lympho-immunoblastic lymphoma, the most frequently affected organ was the lung, and, in almost half of the rats with this diagnosis, the lung was the only affected organ. Lesions diagnosed as lymphoma in published illustrations had pleomorphic cellular morphology and appeared to contain neutrophils. Information from these reports and other sources indicated that lesions typical of M. pulmonis disease were prevalent among the aspartame and MTBE study rats and that the rats were not specific-pathogen-free. Because the lymphoma type, cellular morphology, and organ distribution reported in these studies are atypical of lymphoma in rats, because lymphocyte and plasma cell accumulation in the lung is characteristic of M. pulmonis disease, and because M. pulmonis disease can be exacerbated by experimental manipulations, including chemical treatment, we suggest that a plausible alternative explanation for the reported results of these bioassays is that the studies were confounded by M. pulmonis disease and that lesions of the disease were interpreted as lymphoma.

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“…We included cases with either or both as bronchitis because epithelial hyperplasia is characteristic of respiratory mucosal inflammation induced by M pulmonis. 7,8,[10][11][12]14 Bronchitis and otitis were the most frequently recorded findings. Table 1 shows the occurrence of these lesions.…”

Section: Additional Evidence Of Mycoplasma Pulmonis Diseasementioning

confidence: 99%

Commentary

Schoeb¹,

McConnell

2010

Vet Pathol

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The authors recently assessed the likelihood that lifetime cancer bioassays of aspartame, methanol, and methyl tertiary butyl ether conducted with conventional (not specific pathogen free) Sprague-Dawley rats were compromised by Mycoplasma pulmonis disease. From the tumor data and other information, the authors concluded that the rats used in these bioassays likely had M pulmonis disease and that lesions of the disease were plausibly interpreted as lymphoma. Subsequently, they analyzed the nonneoplastic lesion data from these bioassays for occurrence of inflammatory lesions and found that 2,267 of 2,960 rats (76.6%) were reported to have bronchitis, the signature lesion of M pulmonis disease, and that 633 rats (21.4%) were reported to have otitis, another common lesion of the disease. Also, documentation is now available containing serologic evidence of mycoplasma infection in the rats. In contrast, the reports of 6 National Toxicology Program bioassays based on specific pathogen-free Sprague-Dawley rats listed no instances of bronchitis or otitis. These findings provide substantial additional evidence that the bioassays in question were compromised by M pulmonis disease. Therefore, the reported induction of lymphoma in these studies should not be considered in cancer risk assessments. The authors also found that inflammatory lesions were prevalent in lymph nodes, thymus, pleura, and brain. Finally, they found that of all 328 cases of lymphoimmunoblastic lymphoma affecting the lung (the primary form of lymphoma reported), 218 (66.5%) occurred within the first 104 weeks of the studies, showing that occurrence of such lesions was not due to appearance in rats surviving beyond that interval.

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Murine Respiratory Mycoplasmosis, Rat and Mouse

Cited by 16 publications

References 34 publications

TNF-α drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice

TNF-α drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice

Mycoplasma pulmonis and Lymphoma in Bioassays in Rats

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