Influence of human T lymphotrophic virus type I on diffuse pan-bronchiolitis

Transforming growth factor-β1 (TGF-β1) has been thought to play a key role in the pathogenesis of scleroderma; however, therapeutic approaches targeting TGF-β1 and/or related molecules have provided inconsistent results. In this study, we demonstrate the antifibrotic effects of local administration of latency-associated peptide (LAP), a linker propeptide that specifically converts the active form of TGF-β1 to the inactive from, in the bleomycin (BLM)-induced scleroderma mouse model. Histologically, co-injection of BLM and LAP into the dorsal skin prevented proinflammatory and later sclerotic responses, features seen in mice injected with BLM alone or together with PBS as control. In addition, the skin sites co-injected with BLM and LAP showed a marked decrease in mast cell infiltration. Isoform-specific ELISA and real-time RT-PCR revealed transient decreases in connective tissue growth factor and collagen α1(I) mRNA expression 2 weeks after the co-injection, preceded by a decrease in active TGF-β1 protein production. In contrast, the baseline expression of TGF-β1 mRNA remained unchanged. By contrast, after induction of scleroderma by BLM, the inhibitory effects of LAP did not occur, suggesting time course-dependent TGF-β1 regulation. Our data may have novel therapeutic implications regarding in vivo TGF-β1 inactivation in human scleroderma, and the post-transcriptional interrelationship between major fibrogenic cytokines in the autoimmune aspects of the disease.

Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Local injection of latency‐associated peptide, a linker propeptide specific for active form of transforming growth factor‐beta1, inhibits dermal sclerosis in bleomycin‐induced murine scleroderma

Nakamura-Wakatsuki

Oyama

Yamamoto

2011

“…Myofibroblasts predominate in areas of increased collagen deposition in scleroderma lesional skin, where the number of myofibroblasts correlates with the severity of fibrosis (24), and a-SMA-positive myofibroblasts are increased in the experimental mouse model of bleomycin-induced scleroderma (25). Promotion of myofibroblast accumulation by LPA 1 signalling would therefore be expected to promote dermal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Antifibrotic effect of lysophosphatidic acid receptors LPA₁ and LPA₃ antagonist on experimental murine scleroderma induced by bleomycin

Ohashi

Yamamoto

2015

The study of lysophosphatidic acid (LPA) receptor has recently focused on its involvement in the pathogenesis of systemic sclerosis (SSc). We examined the inhibitory effects of the antagonist for the LPA receptor, a selective LPA1 and LPA3 antagonist (Ki16425), on dermal and lung fibrosis in a mouse model of SSc. Ki16425 was administered intra-dermally after 6 h on the same sites as bleomycin injection. Histopathological examination showed that skin lesions were markedly attenuated by treatment with Ki16425 at doses of 1 and 10 mg/kg, along with reduced dermal thickness. Hydroxyproline contents in the Ki16425-treated skin showed a decrease of 35% (1 mg/kg) and 45% (10 mg/kg) compared with those in the oil-injected skin of the controls. The number of mast cells and phospho-Smad2/3-positive spindle cells of the Ki16425-treated skin was significantly decreased compared with that in the controls. Additionally, RT-PCR analysis showed that the mRNA levels of TGF-β1, CTGF, MIP-1α, IFN-γ and collagen α1(I) were significantly decreased in both the 1-mg/kg and 10-mg/kg groups of the Ki16425-treated mice compared with those in the controls. Furthermore, treatment with bleomycin and Ki16425 showed reduction in lung fibrosis, and the hydroxyproline contents in the lungs of the Ki16425-treated mice showed a decrease of 25% (1 mg/kg) and 32% (10 mg/kg) compared with those in the lungs of the controls. Taken together, Ki16425 was found to improve dermal and lung fibrosis in a mouse model of bleomycin-induced murine scleroderma. These results suggest that Ki16425 has the potential to be an effective new treatment for scleroderma.

“…This suggests a potential therapeutic role for TGF-b and/or TNF-a inhibition in the treatment of both disorders. Interestingly, although TGF-b inhibition prevented skin fibrosis in the graftversus-host disease and bleomycin-induced mouse models of scleroderma (41,42), a placebo-controlled clinical trial evaluating a human antibody to TGF-b in scleroderma showed no evidence of efficacy (43).…”

Section: Discussionmentioning

confidence: 99%

SMAD inhibition attenuates epithelial to mesenchymal transition by primary keratinocytes in vitro

O’Kane

Jackson

Kissenpfennig

et al. 2014

Epithelial to mesenchymal transition (EMT) is a process whereby epithelial cells undergo transition to a mesenchymal phenotype and contribute directly to fibrotic disease. Recent studies support a role for EMT in cutaneous fibrotic diseases including scleroderma and hypertrophic scarring, although there is limited data on the cytokines and signalling mechanisms regulating cutaneous EMT. We investigated the ability of TGF-β and TNF-α, both overexpressed in cutaneous scleroderma and central mediators of EMT in other epithelial cell types, to induce EMT in primary keratinocytes and studied the signalling mechanisms regulating this process. TGF-β induced EMT in normal human epidermal keratinocytes (NHEK cells), and this process was enhanced by TNF-α. EMT was characterised by changes in morphology, proteome (down-regulation of E-cadherin and Zo-1 and up-regulation of vimentin and fibronectin), MMP secretion and COL1α1 mRNA expression. TGF-β and TNF-α in combination activated SMAD and p38 signalling in NHEK cells. P38 inhibition with SB203580 partially attenuated EMT, whereas SMAD inhibition using SB431542 significantly inhibited EMT and also reversed established EMT. These data highlight the retained plasticity of adult keratinocytes and support further studies of EMT in clinically relevant in vivo models of cutaneous fibrosis and investigation of SMAD inhibition as a potential therapeutic intervention.