Blood flowing across microvascular endothelium creates shear forces that must be overcome for lymphocytes to transmigrate into perivascular inflammatory tissues. The applicants propose the hypothesis that these forces are overcome by focal structural adaptations in the inflammatory microcirculation. These inflammation-inducible structural changes in the microcirculation-here referred to as microangiectasis-provide a mechanism for the controlled, localized creation of hemodynamic conditions suitable for lymphocyte adhesion and transmigration. Since these conditions must exist wherever lymphocytic inflammation occurs, the applicants propose that comparable structural changes exist in the systemic and pulmonary inflammatory microcirculation. To test these predictions, the applicants propose a combination of structural and functionall studies of microangiectasias in the skin, lung, gut and liver microcirculation. Corrosion casting and 3-dimensional scanning electron microscopy will be used to visualize and quantify the structural morphology of microangiectasias in the inflammatory microcirculation. The functional endpoint of microangiectasias, the transmigration of lymphocytes into extravascular tissues, will be investigated by both tissue cytometry and intravital microscopy. The applicants' preliminary intravital microscopy observation suggest that the motion of lymphocytes in microangiectasias is irregular and disordered; thus, the flow, there may be a recirculating (vortex) flow region in the microangiectasia dominating the motion of migrating cells. To investigate these possibilities, the applicants propose to study the carrier fluid mechanics and the motion of lymphocytes in the microangiectasias using computational fluid dynamic modeling. Finally, the applicants' studies of """"""""normal"""""""" lymphocytic inflammation will be extended to a genetically engineered model of focal vascular dilatations. The Endoglin hyploinsufficiency mouse, a model of the human disease hereditary hemorrhagic telangiectasias, demonstrates focal vascular dilatations that appear to be the pathologic manifestation of microangiectasias. The discovery of focal structural adaptations that regulate tissue entry in lymphocytic inflammation has immediate relevance for many areas of vascular biology and adds a new dimension to our understanding of inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075426-04
Application #
7114989
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S1))
Program Officer
Sarkar, Rita
Project Start
2003-09-26
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2009-08-31
Support Year
4
Fiscal Year
2006
Total Cost
$326,157
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Gibney, Barry C; Wagner, Willi L; Ysasi, Alexandra B et al. (2017) Structural and functional evidence for the scaffolding effect of alveolar blood vessels. Exp Lung Res 43:337-346
Wagner, Willi; Bennett, Robert D; Ackermann, Maximilian et al. (2015) Elastin Cables Define the Axial Connective Tissue System in the Murine Lung. Anat Rec (Hoboken) 298:1960-8
Filipovic, Nenad; Gibney, Barry C; Nikolic, Dalibor et al. (2014) Computational analysis of lung deformation after murine pneumonectomy. [corrected]. Comput Methods Biomech Biomed Engin 17:838-44
Ackermann, Maximilian; Houdek, Jan P; Gibney, Barry C et al. (2014) Sprouting and intussusceptive angiogenesis in postpneumonectomy lung growth: mechanisms of alveolar neovascularization. Angiogenesis 17:541-51
Filipovic, Nenad; Gibney, Barry C; Kojic, Milos et al. (2013) Mapping cyclic stretch in the postpneumonectomy murine lung. J Appl Physiol (1985) 115:1370-8
Ackermann, Maximilian; Tsuda, Akira; Secomb, Timothy W et al. (2013) Intussusceptive remodeling of vascular branch angles in chemically-induced murine colitis. Microvasc Res 87:75-82
Ysasi, Alexandra B; Belle, Janeil M; Gibney, Barry C et al. (2013) Effect of unilateral diaphragmatic paralysis on postpneumonectomy lung growth. Am J Physiol Lung Cell Mol Physiol 305:L439-45
Chamoto, Kenji; Gibney, Barry C; Ackermann, Maximilian et al. (2013) Alveolar epithelial dynamics in postpneumonectomy lung growth. Anat Rec (Hoboken) 296:495-503
Chamoto, Kenji; Gibney, Barry C; Lee, Grace S et al. (2013) Migration of CD11b+ accessory cells during murine lung regeneration. Stem Cell Res 10:267-77
Chamoto, Kenji; Gibney, Barry C; Ackermann, Maximilian et al. (2012) Alveolar macrophage dynamics in murine lung regeneration. J Cell Physiol 227:3208-15

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