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Rat lungs were exposed to oxygen to determine the expression of messenger ribonucleic acid and transforming growth factor-beta (TGF-beta) during oxygen-induced pulmonary injury. Analysis of pulmonary injury in rat lungs by TGF-beta immunostaining indicated the presence of increased levels of TGF-beta isoforms. The bronchiolar epithelium also expressed elevated levels of TGF-beta2 and TGF-beta3 due to cell-type specific alterations in TGF-beta expression during pulmonary oxygen exposure.

Modified activation of transforming growth factor-beta (TGF-beta)1-3 activity during bleomycin-incited lung injury by type II alveolar epithelial cells modulates proliferation of pulmonary alveolar epithelial cells during injury and repair. Synthesis of endogenous TGF-beta by alveolar epithelial cells has a significant function in the injured lung epithelium remodeling. TGF-beta3 and TGF-beta2 are present in all smooth muscle-, endothelial- and pulmonary epithelial cells in the lungs of both bleomycin-treated and normal rats.

Experimental synthesis and analysis of two mutant transforming growth factor-beta (TGF-beta) molecules, TGF-beta1 (Delta69-73) and TGF-beta1 (71 Trp), reveal that the two mutant molecules have distinct biological properties and modifications in the amino acid 71 region influence the receptor binding activity of TGF-beta. TGF-beta1 (Delta69-73) is a less potent suppressor of colorectal cancer cells than TGF-beta1 (71 Trp) and less potent regulator of carcino embryonic antigen mRNA than TGF-beta1 (71 Trp). TGF-beta1 (71 Trp) binds strongly to Mv1Lu and LS1034 cell receptors while both exhibit similar bindings properties to type II receptor.

An in vitro model of rat epiphyseal chrondrocyte differentiation in which cells are held in a three-dimensional cell pellet was used to demonstrate that exogenous transforming growth factor-beta 1 (TGF-beta 1) impedes terminal differentiation of epiphyseal chondrocytes into hypertrophic cells. The TGF-beta 1 involved in endochondral ossification controls the chondrocyte development and differentiation by modulating the comparative expression of cartilage matrix proteins and metalloproteases. The role of TGF-beta 1 shows that a single peptide growth faction can direct the control of various cellular mechanism such as cell development and differentiation, matrix degradation and matrix synthesis at the molecular level.

The expression of transforming growth factor beta-1 (TGF-beta 1) and TGF-beta 2, between low-and high-risk papillomas at initial and late times after tumor emergence, was compared to analyze the potential function of TGF-beta as a risk factor in tumor progression and malignant conversion. Alterations in TGF-beta expression were correlated with modified proliferation in low-and high-risk tumors and with the expression of identified markers of malignant progression, by using 5-bromo-2'-deoxyuridine (BrdUrd). Cell proliferation in the epidermis of TGF-beta 1 null mice were analyzed to conform a basic association between variations in TGF-beta expression and epidermal cell proliferation.

Transgenic mouse lines harboring null mutations in the transforming growth factor-beta-1 (TGF-beta-1) locus were generated to elucidate the physiological role of this isoform of TGF-beta. The homozygous mutants exhibited high intrauterine lethality and the surviving mice had widespread inflammatory reactions in various organs causing death at around three to four weeks. The results indicate that TGF-beta-1 is involved in processes such as inflammation, tissue repair, autoimmune disease and allograftrejection.

The intracellular signaling mechanisms through which TGF-β regulates pulmonary development are incompletely understood. Canonical TGF-β signaling involves Smad2/3 phosphorylation, Smad2/3-Smad4 complex formation and nuclear localization, and gene regulation. Here, we show that physiologically relevant TGF-β1 levels also stimulate Smad1/5 phosphorylation, which is typically a mediator of bone morphogenetic protein (BMP) signaling, in mouse pup pulmonary artery smooth muscle cells (mPASMC) and lung fibroblasts and other interstitial lung cell lines. This cross-talk mechanism likely has in vivo relevance because mixed Smad1/5/8-Smad2/3 complexes, which are indicative of TGF-β-stimulated Smad1/5 activation, were detected in the developing mouse lung using a proximity ligation assay. Although mixed Smad complexes have been shown not to transduce nuclear signaling, we determined that TGF-β stimulates nuclear localization of phosphorylated Smad1/5 and induces the expression of prototypical BMP-regulated genes in the mPASMC. Small-molecule kinase inhibitor studies suggested that TGF-β-regulated Smad1/5 phosphorylation in these cells is mediated by TGF-β-type I receptors, not BMP-type I receptors, but possibly the accessory activin-like kinase (ALK1) receptor. Although work by others suggested that ALK1 is expressed exclusively in endothelial cells in the vasculature, we detected ALK1 mRNA and protein expression in mPASMC in vitro and in mouse pup lungs. Moreover, using an antimurine ALK1 antibody and mPASMC, we determined that ALK1 regulates Smad1/5 phosphorylation by TGF-β. Together, these studies characterize an accessory TGF-β-stimulated BMP R-Smad signaling mechanism in interstitial cells of the developing lung. They also indicate the importance of considering alternate Smad pathways in studies directed at determining how TGF-β regulates newborn lung development. [ABSTRACT FROM AUTHOR]

To investigate the effects of loss of transient receptor potential vanilloid receptor 1 (TRPV1) on the development of neovascularization in corneal stroma in mice. Blocking TRPV1 receptor did not affect VEGF-dependent neovascularization in cell culture. Lacking TRPV1 inhibited neovascularization in corneal stroma following cauterization. Immunohistochemistry showed that immunoreactivity for active form of TGFβ1 and VEGF was detected in subepithelial stroma at the site of cauterization in both genotypes of mice, but the immunoreactivity seemed less marked in mice lacking TRPV1. mRNA expression of VEGF and TGFβ1 in a mouse cornea was suppressed by the loss of TRPV1. TRPV1 gene ablation did not affect invasion of neutrophils and macrophage in a cauterized mouse cornea. Blocking TRPV1 signal does not affect angiogenic effects by HUVECs in vitro. TRPV1 signal is, however, involved in expression of angiogenic growth factors in a cauterized mouse cornea and is required for neovascularization in the corneal stroma in vivo. [ABSTRACT FROM AUTHOR]