Preferential Lymphatic Growth in Bronchus-Associated Lymphoid Tissue in Sustained Lung Inflammation

Abstract

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.

Thy1+IL-7+lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation

“…Increased lymphatics were also observed in human and mouse iBALT. This is consistent with the previous findings that influenza virus infection-induced iBALT areas have Lyve-1 + lymphatic vessels (8), and robust lymphangiogenesis occurs after iBALT formation in the lungs of mice (55). In addition, increased M2A + lymphatic vessels were observed in lung biopsies from patients with rheumatoid arthritis (13).…”

Precision-cut Mouse Lung Slices to Visualize Live Pulmonary Dendritic Cells

“…These mAbs are therefore of limited practical use for specifically identifying lymphatic vessels in PCLS. However, mAbs to CD90.2 (Thy1.2), a well-known T cell marker, labeled lymphatic structures, as shown previously in other tissues 19,20 (Figures 3A, 3B), as did TdTomato fluorescent protein encoded by a transgene under transcriptional control of the Prox1 promoter 21 (Figure 3A, 3C). PROX1 is a master transcription factor that is necessary for lymphangiogenesis 22 .…”

Lymphangiogenesis in rat asthma model

“…Figure 2 shows representative examples of standard histologic sections (H&E) of the bronchovascular interstitial space from control (PBS) and HDM exposed rats. In the HDM exposed rats, the mass of dark staining inflammatory cells marks bronchus-associated lymphoid tissue (26, 34). Small bronchial arteries (red arrows) are prominent in this region of the airway wall.…”

“…Within the lung, however, few studies have explored this process. The McDonald laboratory, in a series of elegant studies, have documented the process of lymphangiogenesis in the trachea after ovalbumin sensitization (12) and more extensively, bacterial infection (32-34). During these inflammatory conditions, new lymphatic vessels arise in conjunction with new tracheal blood vessels, and their growth appears to be dependent on VEGF-C/D and VEGFR3 (32), TNF-α (35) and IL-β (36).…”