Microvascular Remodelling In Chronic Airway Inflammation In Mice

Thurston, Gavin; Maas, Kevin; LaBarbara, Allyson; McLean, John W.; McDonald, Donald M.

doi:10.1046/j.1440-1681.2000.03342.x

Cited by 29 publications

(23 citation statements)

References 19 publications

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“…Rapid and complete reversal of blood vessel changes in M. pulmonis-infected airways is achievable by elimination of the disease by antibiotics (5). Partial reversal occurs after treatment with the antiinflammatory steroid dexamethasone (7). Newly formed lymphatics appear to be more resistant to reversal (5).…”

Section: Discussionmentioning

confidence: 99%

“…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 airways of mice with M. pulmonis infection is enlargement of capillaries into venules (1,7). The enlargement results from endothelial cell proliferation, not merely vasodilatation (8), but the mediators that drive this change are unknown.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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%

Section: Introductionmentioning

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

View full text Add to dashboard Cite

show abstract

“…30,34 In the process, capillaries acquire a venular phenotype, reflected by increased immunoreactivity for multiple molecules typical of venules, including P-selectin, E-selectin, ICAM-1, and EphB4, that supports leukocyte adherence and migration and other venulespecific features of the inflammatory response. 28,34,35 Gene expression arrays have documented the increase in expression of leukocyte adhesion molecules at 1 and 12 weeks after infection (at 1 week: P-selectin, 10-fold; E-selectin, 43-fold; and ICAM-1 fourfold compared to pathogen-free; McDonald and Thurston, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin-2-Driven Vascular Remodeling in Airway Inflammation

Tabruyn

Colton

Morisada

et al. 2010

The American Journal of Pathology

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Vascular remodeling is a feature of chronic inflammation during which capillaries transform into venules that expand the region of the vasculature in which leakage and leukocyte emigration both occur. Recently, we found that angiopoietin/Tie2 receptor signaling drives the transformation of capillaries into venules at an early stage of the sustained inflammatory response in the airways of mice infected with Mycoplasma pulmonis. However, the precise contributions of both angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) are not clear. In this study, we sought to determine the contribution of Ang2 to this vascular remodeling. Ang2 mRNA expression levels increased and phosphorylated Tie2 immunoreactivity in mucosal blood vessels decreased, indicative of diminished receptor signaling after infection. Selective inhibition of Ang2 throughout the infection by administration of either of two distinct functionblocking antibodies reduced the suppression of Tie2 phosphorylation and decreased the remodeling of mucosal capillaries into venules, the amount of leukocyte influx, and disease severity. These findings are consistent with Ang2 acting as an antagonist of Tie2 receptors and the reduction of Tie2 phosphorylation in endothelial cells rendering the vasculature more responsive to cytokines that promote both vascular remodeling and the consequences of inflammation after M. pulmonis infection. By blocking such changes, Ang2 inhibitors may prove beneficial in the treatment of sustained inflammation in which vascular remodeling, leakage, and leukocyte influx contribute to its pathophysiology.

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“…3D). To confirm that verge mRNA is expressed in endothelial cells, dual fluorescent labeling was performed using the BS-1, which selectively binds endothelial cells (Thurston et al, 2000). Verge mRNA colocalized with BS-1 in isolated brain capillaries prepared from rats treated with cycloheximide ( Fig.…”

Section: Verge Is Rapidly Induced In Endothelial Cells Of Cerebral Vementioning

confidence: 96%