All- trans -Retinoic Acid Prevents Radiation- or Bleomycin-induced Pulmonary Fibrosis
Although radiotherapy is effective in treating lung cancers, resultant pulmonary injury is the main obstacle. Pulmonary fibrosis is characterized by progressive worsening in pulmonary function leading to high incidence of death. Currently, however, there has been little progress in effective preventive and therapeutic strategies.
Previously, we reported that all-trans-retinoic acid (ATRA) reduced both irradiation-induced interleukin (IL)-6 production in lung fibroblasts and IL-6-dependent cell growth, and also directly inhibited the proliferation of lung fibroblasts after irradiation. In this study, we examined the preventive effect of ATRA on the progression of lung fibrosis both in irradiated and bleomycin-treated mice.
We performed histologic examinations and quantitative measurements of IL-6, transforming growth factor (TGF)-beta(1), and collagen type Ialpha1 (COL1A1) in irradiated and bleomycin- treated mouse lung tissues with or without the administration of ATRA.
Lethal irradiation effect was reduced by intraperitoneal administration of ATRA, and the overall survival rate at 16 wk was 30.0% without ATRA (n = 11), whereas it was 81.8% (n = 10) in the treatment group (p = 0.04). In vitro studies disclosed that the administration of ATRA reduced (1) irradiation-induced production of IL-6, TGF-beta(1), and collagen from IMR90 cells, and (2) IL-6-dependent proliferation and TGF-beta(1)-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of ATRA on lung fibrosis. Furthermore, ATRA ameliorated bleomycin-induced fibrosis in mouse lung tissues.
These data may provide a rationale to explore clinical use of ATRA for the prevention of radiation-induced lung fibrosis and other pathologic conditions involving pulmonary fibrosis.
Available from: Mohammad Reza Keramati
- "The inflammation process leads to the release of cytokines including interleukin-6 (IL-6), which operates through specific hepatic receptors to prevent the synthesis of albumin. On the other hand, IL-6, through a positive autocrine feedback loop, stimulates the proliferation of lung fibroblasts. "
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ABSTRACT: Sulfur mustard (SM) is an incapacitating chemical warfare agent, which has been widely employed in particular regions including Iran. We investigated and reported delayed biochemical and hematological complications of SM in severely toxic Iranian veterans 23 years after exposure.
Forty-two Iranian veterans, residents of Khorasan Razavi, poisoned by SM, and suffering from clinical complications were investigated. A total of 30 healthy male volunteers were also selected as a control group. Biochemical and hematological variables were measured for the case and control groups. Data were analyzed using a Student's t-test by InStat software (GraphPad Inc., San Diego, CA) to determine significant differences between the data from the two groups.
The percentages of reticulocytes were significantly higher in patients (0.82 ± 0.04, P < 0.05). Total protein and albumin levels were significantly lower in veterans (total protein: 7.58 ± 0.07 g/dL, albumin: 4.97 ± 0.04 g/dL, P < 0.01). In addition, we observed a significant increase in serum cholesterol (226.74 ± 5.23 mg/dL, P < 0.01), triglyceride (173.53 ± 17.05 mg/dL, P < 0.05), and gamma-glutamyl transferase (GTT) activity of the patients (44.04 ± 3.35 IU/L, P < 0.05).
Results showed that SM can cause long-term effects on some biochemical factors of veterans. As many of the functional tests of liver and kidney between two groups were statistically unchanged, it seems that the observed biochemical changes may be secondary to delayed respiratory complications of the patients.
Available from: europepmc.org
- "However, 20% of these patients develop radiation-induced pulmonary injury (RILI). The effectiveness of radiotherapy for thoracic malignancies is limited by the occurrence of RILI, which has no effective treatment or prophylaxis yet. RILI is usually divided into two stages, namely, early radiation pneumonitis and late fibrosis. "
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ABSTRACT: Radiation-induced lung injury (RILI) is the most common, dose-limiting complication in thoracic malignancy radiotherapy. Considering its negative impact on patients and restrictions to efficacy, the mechanism of RILI was studied.
Wistar rats were locally irradiated with a single dose of 0, 16, and 20 Gy to the right half of the lung to establish a lung injury model. Two and six months after irradiation, the right half of the rat lung tissue was removed, and the concentrations of TGF-β1, angiotensin II, and aldosterone were determined via enzyme-linked immunosorbent assay.
Statistical differences were observed in the expression levels of angiotensin II and aldosterone between the non-irradiation and irradiation groups. Moreover, the expression level of the angiotensin II-aldosterone system increased with increasing doses, and the difference was still observed as time progressed.
Angiotensin II-aldosterone system has an important pathophysiological function in the progression of RILI.
Available from: Mario Ricciardi
- "Moreover, it has been recently shown that RA, when administered to adult animals, triggers some genes normally active during lung development, thus ameliorating both functions and structure of damaged lung –. Finally, retinoids are molecular inducers of cell differentiation in many organs and may influence the expression of intermediate filaments such as keratins in different cell types –, including MSCs and embryonic stem cells , ; in addition, RA can reduce the fibrosis occurring after lung injury by down-regulating cytokine secretion and directly inhibiting the proliferation of fibroblasts , . "
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ABSTRACT: Mesenchymal stromal cells (MSCs) reside in many organs including lung, as shown by their isolation from fetal lung tissues, bronchial stromal compartment, bronchial-alveolar lavage and transplanted lung tissues. It is still controversial whether lung MSCs can undergo mesenchymal-to-epithelial-transition (MET) and possess immune regulatory properties. To this aim, we isolated, expanded and characterized MSCs from normal adult human lung (lung-hMSCs) and compared with human bone marrow-derived MSCs (BM-hMSCs). Our results show that lung-MSCs reside at the perivascular level and do not significantly differ from BM-hMSCs in terms of immunophenotype, stemness gene profile, mesodermal differentiation potential and modulation of T, B and NK cells. However, lung-hMSCs express higher basal level of the stemness-related marker nestin and show, following in vitro treatment with retinoic acid, higher epithelial cell polarization, which is anyway partial when compared to a control epithelial bronchial cell line. Although these results question the real capability of acquiring epithelial functions by MSCs and the feasibility of MSC-based therapeutic approaches to regenerate damaged lung tissues, the characterization of this lung-hMSC population may be useful to study the involvement of stromal cell compartment in lung diseases in which MET plays a role, such as in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.
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