“Interface of TH2 Inflammation and TGF-beta Signaling in Pulmonary Hypertension” – A Synopsis

Below is a synopsis of this video “Interface of TH2 Inflammation and TGF-beta Signaling in Pulmonary Hypertension”, a talk by Rubin Tuder given at the Vera Moulton Wall Center for Pulmonary Vascular Disease:


  • He has shown the first statistical correlation of perivascular inflammation with mPAP and vascular remodeling (~60 lungs from IPAH, hereditary PAH, scleroderma associated PH) despite current PH drugs:

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  • Schistosomiasis – 200 million people infected by parasite – in temperate areas like China, Brazil, Sudan, etc. 1-10% of people infected will develop PH
  • Rather than talking about things where we don’t know what the cause/effect relationship is in PH (IPAH, Scleroderma, etc.), we should start with Schistosomiasis, which is something where we know what the culprit is: an egg nesting around vasculature that causes vasculopathy.
  • In humans, the timespan for development of PH from Schisto is about 2 years: there are probably recurrent nesting of eggs in pulmonary circulation.
  • The mechanism:

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  • Schisto is a complex organism… if you define the antigen causing it specifically you can proceed in a more detailed manner.
  • Need both IL-4 and IL-13 for this process to occur, these primarily come from CD4 cells
  • There are good guys and bad guys in the immune system, and like in life, some good guys can become bad guys and vice versa
  • TGF-beta1 resides in the lung in the matrix. It anchors into the fibrillin network of the lung… this keeps it in an inactive state
  • Thrombospondin-1 (TSP-1) is capable of releasing TGF-beta1 from the matrix and allows it to be functional.
  • TSP-1 is upregulated in the Schistosomiasis induced PH mouse
  • If you block the TSP-1 action on TGF-beta1, you improve the hemodynamics of the mouse, as well as vascular remodeling
  • TSP-1 comes from the bone marrow compartment
  • When you deplete the macrophage and monocyte population with clodronate, you have a decrease in pulmonary artery pressure, but no impact in terms of remodeling.
  • All of this is evidence suggesting that the macrophage and monocyte population from the bone marrow is possibly activating TSP-1 to induce PH
  • Antifibrotic therapies: TGF-beta targeting is still not in the clinic because it has enormous toxicity, it shuts down the kidney, it causes autoimmune disease because it is a suppressant for T Cells. Instead you should go for the mechanism by which TGF-beta is activated in the context of the disease you are studying. In this case, it is the macrophage population activating TSP-1.
  • All of these results from animal studies have been validated in human lung tissue.
  • To really prove that this is an immune mediated process, you need to prove that this whole process is induced by a specific antigen or set of antigens, rather than from the parasite egg.
  • Intimal remodeling is not a prominent feature of PH in the mouse, most remodeling is in the media, because the intima of the mouse is not that robust. There is some remodeling of the intima, but it does not occlude the vascular lumen.
  • Spironolactone, which is being used to treat PH, has some impact on vascular intimal fibrosis.
  • In PH, regardless of which comes first, you have both media and intima thickening and remodeling, but these dance together. If you potentially stop one, you can “stop the dancing”.
  • Eosinophils are also present in this Schisto model, but they likely do not play a role in disease progression.
  • PH is a two hit process: in Schisto you need both the parasite, but also another stressor to induce to macrophage/monocyte TSP-1 activating population to arise and do damage.

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