Lymphangiogenesis is a recognized hallmark of inflammatory processes in tissues and organs as diverse as the skin, heart, bowel, and airways. In clinical and animal models wherein the signaling processes of lymphangiogenesis are manipulated, most studies demonstrate that an expanded lymphatic vasculature is necessary for the resolution of inflammation. The fundamental roles that lymphatics play in fluid clearance and immune cell trafficking from the periphery make these results seemingly obvious as a mechanism of alleviating locally inflamed environments: the lymphatics are simply providing a drain. Depending on the tissue site, lymphangiogenic mechanism, or induction timeframe, however, evidence shows that inflammation-associated lymphangiogenesis (IAL) may worsen the pathology. Recent studies have identified lymphatic endothelial cells themselves to be local regulators of immune cell activity and its consequential phenotypes – a more active role in inflammation regulation than previously thought. Indeed, results focusing on the immunocentric roles of peripheral lymphatic function have revealed that the basic drainage task of lymphatic vessels is a complex balance of locally processed and transported antigens as well as interstitial cytokine and immune cell signaling: an interplay that likely defines the function of IAL. This review will summarize the latest findings on how IAL impacts a series of disease states in various tissues in both preclinical models and clinical studies. This discussion will serve to highlight some emerging areas of lymphatic research in an attempt to answer the question relevant to an array of scientists and clinicians of whether IAL helps to fuel or extinguish inflammation. Impact statement Inflammatory progression is present in acute and chronic tissue pathologies throughout the body. Lymphatic vessels play physiological roles relevant to all medical fields as important regulators of fluid balance, immune cell trafficking, and immune identity. Lymphangiogenesis is often concurrent with inflammation and can potentially aide or worsen disease progression. How new lymphatic vessels impact inflammation and by which mechanism is an important consideration in current and future clinical therapies targeting inflammation and/or vasculogenesis. This review identifies, across a range of tissue-specific pathologies, the current understanding of inflammation-associated lymphangiogenesis in the progression or resolution of inflammation.

See editorial article: Wiig H. 2021. As for blood vessels, the answer regarding lymphatics is often NO. Acta Physiol (Oxf). e13697 Gaurav Baranwal and Heidi A. Creed have equal contribution.

We developed an elective course titled Medicine in Extreme Environments (MEE) at the University of Texas Southwestern Medical Center for firstand second-year medical students. This course covered physiology, research, clinical practice, and career guidance regarding the fields of wilderness, space, hyperbaric, combat, and exercise medicine. The primary aim was to generate interest in and awareness of these seldom covered fields of medicine by exposing medical students to these disciplines during their preclinical years. A postcourse questionnaire was implemented to investigate whether the MEE course increased awareness of, interest in, and knowledge in the fields of medicine included in the curriculum. Through 2 iterations of the class, a total of 67 students enrolled in the course, and 38 students completed the questionnaire. After course completion, 95% felt they better understood the work and lifestyle of the fields covered, 100% learned more about concepts of each field, and 74% agreed that the elective influenced the direction of their future careers to include some part of the fields emphasized. Although only a limited number of students enrolled in this course, these initial findings suggest that the MEE curriculum may have some utility in promoting awareness of and interest in these medical disciplines among students who attend the course. With continued student and faculty support, this course will likely be continued annually at our institution. We believe that certain aspects of this course may be useful in helping develop similar courses at other medical schools.

Transport of fluid and macromolecules from the interstitium into lymphatic vessels is necessary for maintaining tissue homeostasis. Lymphatic capillary structure suggests that passive, paracellular transport would be the predominate route of macromolecule entry into lymphatics. Active transcellular transport, however, was recently identified to be equally important to solute flux across lymphatic endothelium in vitro. To specifically test if loss of caveolar transport impacted lymphatic transport, lymphatic conductance and permeability were measured in mice with a global deletion of caveolin‐1 (“CavKO”), the scaffolding protein necessary for caveolae formation, and in mice with a lymphatic endothelial cell‐specific deletion of caveolin‐1 (Lyve1‐Cre x Cav1flox/flox; “LyCav”). In each mouse line, lymphatic capillary architecture was largely unchanged. Using a quantitative microlymphangiography model, lymphatic conductance (mm3 fluid uptake/mm3 tissue/time) was measured to be significantly higher in CavKO mice. Increased lymphatic conductance was also measured in CavKO mice following nitric oxide synthase inhibition and in LyCav mice with lymphatic‐specific loss of caveolae. The permeability to 70kDa dextran was significantly increased in monolayers of lymphatic endothelial cells isolated from CavKO mice. These findings confirm that macromolecule transport is increased with loss of caveolar trafficking. Interestingly, macromolecule transport within the lymphatic system, measured by transit rate of dextran to a sentinel lymph node, was significantly reduced in CavKO and LyCav mice and isolated vessel studies identified increased permeability of CavKO collecting lymphatic vessels resulting in macromolecule loss from the lumen. These studies identify lymphatic caveolar biology as a key regulator of active lymphatic transport functions. Support or Funding Information This research was supported by the Texas A&M University College of Medicine and Department of Medical Physiology.