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of the remodeling, capillaries enlarge and transform into venules that contribute to leukocyte adhesion and migration unpublished observations).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 ...

Angiogenesis and lymphangiogenesis participate in many inflammatory diseases , and their reversal is thought to be beneficial. However , the extent of reversibility of vessel remodeling is poorly understood. We exploited the potent anti-inflammatory effects of the corticosteroid dexamethasone to test the preventability and reversibility of vessel remodeling in Mycoplasma pulmonis-infected mice using immunohistochemistry and quantitative RT-PCR. In this model robust immune responses drive rapid and sustained changes in blood vessels and lymphatics. In infected mice not treated with dexamethasone , capillaries enlarged into venules expressing leukocyte adhesion molecules , sprouting angiogenesis and lymphangiogenesis occurred , and the inflammatory cytokines tumor necrosis factor and interleukin-1 increased. Concurrent dexamethasone treatment largely prevented the remodeling of blood vessels and lymphatics. Dexamethasone also significantly reduced cytokine expression , bacterial burden , and leukocyte influx into airways and lungs over 4 weeks of infection. In contrast , when infection was allowed to proceed untreated for 2 weeks and then was treated with dexamethasone for 4 weeks , most blood vessel changes reversed but lymphangiogenesis did not , suggesting that different survival mechanisms apply. Furthermore , dexamethasone significantly reduced the bacterial burden and influx of lymphocytes but not of neutrophils or macrophages or cytokine expression. These findings show that lymphatic remodeling is more resistant than blood vessel remodeling to corticosteroid-induced reversal. We suggest that lymphatic remodeling that persists after the initial inflammatory response has resolved may influence subsequent inflammatory episodes in clinical situations. (Am J

Lymphatics proliferate, become enlarged, or regress in multiple inflammatory lung diseases in humans. Lymphatic growth and remodeling is known to occur in the mouse trachea in sustained inflammation, but whether intrapulmonary lymphatics exhibit similar plasticity is unknown. We examined the time course, distribution, and dependence on vascular endothelial growth factor receptor (VEGFR)-2/VEGFR-3 signaling of lung lymphatics in sustained inflammation. Lymphatics in mouse lungs were examined under baseline conditions and 3 to 28 days after Mycoplasma pulmonis infection, using prospero heomeobox 1-enhanced green fluorescence protein and VEGFR-3 as markers. Sprouting lymphangiogenesis was evident at 7 days. Lymphatic growth was restricted to regions of bronchus-associated lymphoid tissue (BALT), where VEGF-C-producing cells were scattered in T-cell zones. Expansion of lung lymphatics after infection was reduced 68% by blocking VEGFR-2, 83% by blocking VEGFR-3, and 99% by blocking both receptors. Inhibition of VEGFR-2/VEGFR-3 did not prevent the formation of BALT. Treatment of established infection with oxytetracycline caused BALT, but not the lymphatics, to regress. We conclude that robust lymphangiogenesis occurs in mouse lungs after M. pulmonis infection through a mechanism involving signaling of both VEGFR-2 and VEGFR-3. Expansion of the lymphatic network is restricted to regions of BALT, but lymphatics do not regress when BALT regresses after antibiotic treatment. The lung lymphatic network can thus expand in sustained inflammation, but the expansion is not as reversible as the accompanying inflammation.

No abstract

No abstract