Increased fibroblast telomerase expression precedes myofibroblast α-smooth muscle actin expression in idiopathic pulmonary fibrosis

OBJECTIVE: This study sought to identify the relationship between fibroblast telomerase expression, myofibroblasts, and telomerase-mediated regulatory signals in idiopathic pulmonary fibrosis. METHODS: Thirty-four surgical lung biopsies, which had been obtained from patients with idiopathic pulmonary fibrosis and histologically classified as usual interstitial pneumonia, were examined. Immunohistochemistry was used to evaluate fibroblast telomerase expression, myofibroblast α-smooth muscle actin expression and the tissue expression of inter leu kin-4, transforming growth factor-β, and basic fibroblast growth factor. The point-counting technique was used to quantify the expression of these markers in unaffected, collapsed, mural fibrosis, and honeycombing areas. The results were correlated to patient survival. RESULTS: Fibroblast telomerase expression and basic fibroblast growth factor tissue expression were higher in collapsed areas, whereas myofibroblast expression and interleukine-4 tissue expression were higher in areas of mural fibrosis. Transforming growth factor-β expression was higher in collapsed, mural fibrosis and honeycombing areas in comparison to unaffected areas. Positive correlations were found between basic fibroblast growth factor tissue expression and fibroblast telomerase expression and between interleukin-4 tissue expression and myofibroblast α-smooth muscle actin expression. Negative correlations were observed between interleukin-4 expression and basic fibroblast growth factor tissue expression in areas of mural fibrosis. Myofibroblast α-smooth muscle actin expression and interleukin-4 tissue expression in areas of mural fibrosis were negatively associated with patient survival. CONCLUSION: Fibroblast telomerase expression is higher in areas of early remodeling in lung tissues demonstrating typical interstitial pneumonia, whereas myofibroblast α-smooth muscle actin expression predominates in areas of late remodeling. These events seem to be regulated by basic fibroblast growth factor and interleukin-4 tissue expression, respectively

Adiaspiromycosis of an Apodemus agrarius captured wild rodent in Korea

Adiaspiromycosis is caused by pulmonary infection with Emmonsia. Inhalated spores of Emmonsia cause asymptomatic infection to necrogranulomatous pneumonia, depending on the burden of adiaspore and host immunity. For disease monitoring of wild rodents captured on Jeju Island in Korea, we examined the lung tissue of wild rodents histopathologically. Spores composed of thick three-layered walls were found following histopathological examination and were diagnosed as adiaspiromycosis. Adiaspiromycosis has been found in mammals in many parts of the world. To our knowledge, this is the first report of adiaspiromycosis of an Apodemus agrarius captured in Korea

Increased fibroblast telomerase expression precedes myofibroblast alpha-smooth muscle actin expression in idiopathic pulmonary fibrosis

OBJECTIVE: This study sought to identify the relationship between fibroblast telomerase expression, myofibroblasts, and telomerase-mediated regulatory signals in idiopathic pulmonary fibrosis. METHODS: Thirty-four surgical lung biopsies, which had been obtained from patients with idiopathic pulmonary fibrosis and histologically classified as usual interstitial pneumonia, were examined. Immunohistochemistry was used to evaluate fibroblast telomerase expression, myofibroblast alpha-smooth muscle actin expression and the tissue expression of interleukin-4, transforming growth factor-beta, and basic fibroblast growth factor. The point-counting technique was used to quantify the expression of these markers in unaffected, collapsed, mural fibrosis, and honeycombing areas. The results were correlated to patient survival. RESULTS: Fibroblast telomerase expression and basic fibroblast growth factor tissue expression were higher in collapsed areas, whereas myofibroblast expression and interleukine-4 tissue expression were higher in areas of mural fibrosis. Transforming growth factor-beta expression was higher in collapsed, mural fibrosis and honeycombing areas in comparison to unaffected areas. Positive correlations were found between basic fibroblast growth factor tissue expression and fibroblast telomerase expression and between interleukin-4 tissue expression and myofibroblast alpha-smooth muscle actin expression. Negative correlations were observed between interleukin-4 expression and basic fibroblast growth factor tissue expression in areas of mural fibrosis. Myofibroblast alpha-smooth muscle actin expression and interleukin-4 tissue expression in areas of mural fibrosis were negatively associated with patient survival. CONCLUSION: Fibroblast telomerase expression is higher in areas of early remodeling in lung tissues demonstrating typical interstitial pneumonia, whereas myofibroblast alpha-smooth muscle actin expression predominates in areas of late remodeling. These events seem to be regulated by basic fibroblast growth factor and interleukin-4 tissue expression, respectively

Aumento na expressão de telomerase por fibroblastos ocorre precocemente à expressão de alfa-actina de músculo liso por miofibroblastos no processo de remodelamento da pneumonia intersticial usual

Objective: To identify potential markers associated with fibroblast telomerase and interstitial myfibroblast alpha-smooth muscle actin (α-AMS) expression in patients with idiopathic pulmonary fibrosis/usual intersticial pneumonia (IPF/UIP). Methods: Pulmonary specimens included 34 surgical lung biopsies, histologically classified as UIP, from patients clinically diagnosed with IPF. Fibroblast telomerase expression, interstitial myofibroblast α-AMS expression and IL-4 (interleukin 4), TGF-β (transforming growth factor beta) and bFGF (basic fibroblast growth factor) tissue expression were evaluated by immunohistochemistry and quantified in collapsed (COL), mural fibrosis (MF) and honeycombing areas (HC). Results: Telomerase expression was significantly higher in COL areas than in MF and HC areas. The same was observed for b-FGF. Interleukin-4 and α-AMS expression were significantly higher in MF areas. TGF-β expression ws higher in COL and HC areas. We observed a positive correlation between telomerase and bFGF expression in COL, MF and HC areas. The same was noted for α-AMS and IL-4. In MF areas, a negative correlation between IL-4 and b-FGF was obtained and TGF-β tended to positively correlate with α-AMS. In multivariate analysis, IL-4 tissue and α-AMS myofibroblast expression in MF areas were independently predictive of mortality in a statistically significant model including age, tobacco use and FVC (full vital capacity). Patients with IL-4 expression lower than 13.5% in MF areas had better survival. The same was noted for α-AMS expression lower than 8.5%. Conclusion: Fibroblast multiplicative capacity, characterized by telomerase expression and associated with bFGF tissue expression, seems to predominate in the early remodeling process of IPF/UIP, whereas myofibroblast differentiation, characterized by alpha-smooth muscle actin expression and associated with IL-4 tissue expression, seems to lead to the later fibrotic response. Patient survival seems to be influenced by the intensity of this processObjetivo: Identificar potenciais marcadores associados à expressão de telomerase em fibroblastos e de α-actina de músculo liso (α-AMS) em miofibroblastos de pulmões de pacientes com fibrose pulmonar idiopática/pneumonia intersticial usual (FPI/PIU). Métodos: Utilizamos cortes histológicos de 34 biópsias cirúrgicas de pulmão de pacientes com FPI, caracterizados, à histopatologia, pelo padrão de PIU. As expressões de telomerase por fibroblastos, de α-AMS por miofibroblastos e tecidual de interleucina-4 (IL-4), de fator de crescimento transformador-β (TGF- β) e de fator de crescimento de fibroblastos básico (bFGF) foram avaliados por imunohistoquímica e quantificadas pela técnica de contagem de pontos nas áreas pulmonares de colapso (COL), de fibrose mural (FM) e de faveolamento (FV). Resultados: A expressão de telomerase foi significativamente maior nas áreas de COL que nas áreas de FM e FV. O mesmo foi observado para a expressão de bFGF. Interleucina-4 e α-AMS tiveram expressão significativamente maior nas áreas de FM. A expressão de TGF-β foi maior nas áreas de COL e FV. Observamos uma associação positiva entre expressão de telomerase e bFGF nas áreas COL, FM e FV. O mesmo ocorreu com a expressão de α-AMS e IL-4. Nas áreas de FM, houve uma correlação negativa entre IL-4 e bFGF, e TGF-β apresentou tendência a associação positiva com α-AMS. Análise multivariada revelou que a expressão de IL-4 e α-AMS nas áreas de FM são indicadores independentes de menor sobrevida em modelo estatístico significante incluindo idade, tabagismoe FVC (capacidade vital forçada). Pacientes com expressão de IL-4 menor que 13,5% nas áreas de FM apresentaram melhor sobrevida. O mesmo foi observado para expressão de α-AMS menor que 8,5%. Conclusão: Fibroblastos, com capacidade multiplicativa caracterizada pela expressão de telomerase e de bFGF tecidual, tendem a predominar no estágio precoce de remodelamento da FPI/PIU; enquanto a diferenciação de miofibroblastos, caracterizada pela expressão de α-AMS e IL-4, parece ser responsável pelo estágio tardio da resposta fibrótica. A sobrevida dos pacientes parece ser influenciada por tais processo

Novel therapeutic approaches for pulmonary fibrosis

Pulmonary fibrosis represents the end stage of a number of heterogeneous conditions and is, to a greater or lesser degree, the hallmark of the interstitial lung diseases. It is characterized by the excessive deposition of extracellular matrix proteins within the pulmonary interstitium leading to the obliteration of functional alveolar units and in many cases, respiratory failure. While a small number of interstitial lung diseases have known aetiologies, most are idiopathic in nature, and of these, idiopathic pulmonary fibrosis is the most common and carries with it an appalling prognosis – median survival from the time of diagnosis is less than 3 years. This reflects the lack of any effective therapy to modify the course of the disease, which in turn is indicative of our incomplete understanding of the pathogenesis of this condition. Current prevailing hypotheses focus on dysregulated epithelial–mesenchymal interactions promoting a cycle of continued epithelial cell injury and fibroblast activation leading to progressive fibrosis. However, it is likely that multiple abnormalities in a myriad of biological pathways affecting inflammation and wound repair – including matrix regulation, epithelial reconstitution, the coagulation cascade, neovascularization and antioxidant pathways – modulate this defective crosstalk and promote fibrogenesis. This review aims to offer a pathogenetic rationale behind current therapies, briefly outlining previous and ongoing clinical trials, but will focus on recent and exciting advancements in our understanding of the pathogenesis of idiopathic pulmonary fibrosis, which may ultimately lead to the development of novel and effective therapeutic interventions for this devastating condition