Elastin Organization in Ltbp4S,Tgfb2 Lungs Finally, we examined whether the increased TGF B levels associated with decreased alveologenesis might also be the cause for defective elastogenesis in Ltbp4S mice and whether the reduction of TGF B2 levels would improve elastin organization. We found that the elastic selleck inhibitor fiber organization in E18. 5 Ltbp4S,Tgfb2 lungs resembled that in Ltbp4S,Tgfb2 lungs. Thus elastogenesis still appeared to be defective regardless of improved alveolar septation and presumably lower active TGF B levels. Therefore, we suggest that Ltbp 4 plays an important function in elastogenesis distinguishable from its role in the regulation of TGF B tissue levels. Discussion The experiments presented indicate that the loss of LTBP 4 synthesis in Ltbp4S mouse lungs results in increased TGF B signaling and an impairment of terminal air sac development.
Decreasing TGF B expression or Telatinib signaling in vivo either by genetic or by pharmacological intervention meliorated Ltbp4S lung septation. Ltbp4S mice also display an abnormality in lung elastogenesis apparent as early as E14. 5 16. 5, which appeared to be independent of TGF B signaling, as normalization of terminal air sac septation by decreasing TGF B levels did not normalize the defects in elastic fiber structure. Impairment of LTBP function either through null mutations or biochemical inhibition is believed to result in decreased TGF B action because of faulty secretion, impaired localization, or lack of latent TGF B activation. Although blockade of LTBP function may result in decreased signaling in some circumstances, this might not always be the case. It is clear that the SLC can be activated in vivo in the absence of an LTBP, and if sufficient SLC is secreted, it can be activated to provide TGF B signaling.
Moreover, in several systems, the pathological outcomes of interference with TGF B localization have been attributed to excessive TGF B signaling. The clearest example of this are transgenic mice that produce in the epidermis a truncated LTBP 1, which binds to SLC, but cannot localize to the ECM. These animals have an early onset of the catagen

stage of the hair cycle, concordant with increased TGF B signaling. A similar explanation has been proposed for the lung, vascular and muscle abnormalities in patients and mice with Marfan syndrome, which is caused by mutations in fibrillin 1. In this case, LLCs generate abnormally high levels of active TGF B, perhaps because of improper targeting of the LLC to defective microfibrils. Decreasing total TGF B by the administration of either neutralizing antibodies to TGF B or drugs that decrease TGF B signaling prevents the development of pathological changes in the affected tissues.