SUMMARY:A single intratracheal dose of porcine pancreatic elastase, which is cleared from the lung by 24 hours, was administered to wild-type, IL-1 type 1 receptor-deficient, double TNF-␣ (type 1 and type 2) receptor-deficient, and combined TNF-␣ (type 1 receptor) plus IL-1 receptor-deficient mice. The mean linear intercept (Lm) of saline-treated mice was 32(3) m [mean(SE)]. For wild-type elastase-treated mice, Lm was 81(6) m at 21 days versus 52(5) m at 5 days after treatment, indicating that alveolar wall remodeling occurs long after the elastase injury. At 21 days, Lm values were 67(10), 62(3), and 39(5) m in elastase-treated mice deficient in the IL-1 receptor, double TNF-␣ receptors, and combined receptors, respectively. The level of apoptosis assessed by a terminal deoxynucleotidyl transferase-catalyzed in situ nick end-labeling assay was increased at 5 days after elastase treatment and was markedly and similarly attenuated in the IL-1, the double TNF-␣, and the combined receptor-deficient mice. Our results indicate that inflammatory mediators exacerbate elastase-induced emphysema. We estimate that in the combined TNF-␣ ϩ IL-1 receptor-deficient mice, inflammation accounts for about 80% of the emphysema that develops after elastase treatment; decreased apoptosis of lung cells likely contributes to decreased severity of emphysema. (Lab Invest 2002, 82:79 -85). P ulmonary emphysema is defined as abnormal enlargement of respiratory spaces with destruction of the alveolar walls. Experimental evidence supports the concept that alveolar units are damaged when activated macrophages and neutrophils elaborate proteases that degrade elastin and other structural proteins.The proinflammatory cytokines IL-1 and TNF-␣ are released during inflammatory reactions induced by infection or injury. These effecter substances have overlapping biologic functions, suggesting that they share some common signal transduction pathways (Dinarello, 1997;Kusano et al, 1998;Ledgerwood et al, 1999;Muegge et al, 1989; O' Neill and Greene, 1998;Stewart and Marsden, 1995).In experimental animals, IL-1 stimulates several components of the acute-phase response. The cytokine stimulates the expression of metalloproteinase and other enzymes involved in the degradation of connective tissue proteins (Kusano et al, 1998), and it also stimulates apoptosis (Dinarello, 1998). IL-1 utilizes a single signaling receptor to activate two IL-1 receptor-associated kinases (IRAK-1 and IRAK-2), to recruit TNF receptor-associated factor 6 (TRAF6) and activate nuclear factor-B (NF-B) (Cao et al, 1996). Activation of NF-B results in nuclear translocation and alterations in the rate of transcription of certain target genes (Baldwin, 1996;Gilmore, 1999). NF-B also either increases or decreases apoptosis depending on the cell type (Barkett and Gilmore, 1999). IL-1 affects gene transcription via several other transacting factors including transcription factor AP-1 proteins and CCAAT-enhancer binding proteins (C/EBP) (Muegge et al, 1989;Osborn et al, 1989).TNF...
Pulmonary fibrosis is a pathological condition in which lungs become scarred due to the excess extracellular matrix (ECM) deposition and structural alterations in the interstitium of lung parenchyma. Many patients with interstitial lung diseases (ILDs) caused by long-term exposure to toxic substances, chronic infections, or autoimmune responses develop fibrosis. Etiologies for many ILDs are unknown, such as idiopathic pulmonary fibrosis (IPF), a devastating, relentless form of pulmonary fibrosis with a median survival of 2-3 years. Despite several decades of research, factors that initiate and sustain the fibrotic response in lungs remain unclear and there is no effective treatment to block progression of fibrosis. Here we summarize recent findings on the antifibrotic activity of miR-29, a small noncoding regulatory RNA, in the pathogenesis of fibrosis by regulating ECM production and deposition, and epithelial-mesenchymal transition (EMT). We also describe interactions of miR-29 with multiple profibrotic and inflammatory pathways. Finally, we review the antifibrotic activity of miR-29 in animal models of fibrosis and highlight miR-29 as a promising therapeutic reagent or target for the treatment of pulmonary fibrosis.
. NF-B induced by IL-1 inhibits elastin transcription and myofibroblast phenotype. Am J Physiol Cell Physiol 283: C58-C65, 2002; 10.1152/ ajpcell.00314.2001.-Interleukin (IL)-1 released after lung injury regulates the production of extracellular matrix components. We found that IL-1 treatment reduced the rate of elastin gene transcription by 74% in neonatal rat lung fibroblasts. Deletion analysis of the rat elastin promoter detected a cis-acting element located at Ϫ118 to Ϫ102 bp that strongly bound Sp1 and Sp3 but not nuclear factor (NF)-B. This element mediated IL-1-induced inhibition of the elastin promoter. IL-1 treatment did not affect the level of Sp1 but did induce translocation of the p65 subunit of NF-B. Overexpression of p65 decreased elastin promoter activity and markedly reduced elastin mRNA. Immunoprecipitation studies indicated an interaction between the p65 subunit and Sp1 protein. Microarray analysis of mRNA isolated after overexpression of p65 or treatment with IL-1 revealed downregulation of ␣-smooth muscle actin and calponin mRNAs. Expression of these genes is associated with the myofibroblast phenotype. These results indicate that IL-1 activates the nuclear localization of NF-B that subsequently interacts with Sp1 to downregulate elastin transcription and expression of the myofibroblast phenotype. nuclear factor-B; interleukin-1; Sp1 ELASTIN IS a major structural protein in the lung. It is found most notably in alveolar walls and blood vessels. Tropoelastin, a soluble precursor, is synthesized in alveolar structures by interstitial fibroblasts and in vascular tissue by smooth muscle cells (4,34,35). Elastin synthesis in the pulmonary parenchyma of the rodent lung is highest during alveolarization. This process usually begins in the postnatal period and decreases with maturity (4, 25). Disruption of elastin deposition during development results in failure of alveolar formation (19). In the adult lung parenchyma, elastin mRNA is minimally expressed in interstitial structures but can be reactivated during the development of pulmonary emphysema or fibrosis (18,20).We previously reported (20) that elastin and collagen mRNA levels are upregulated after bleomycin treatment of rodent lungs. This expression was confined primarily to myofibroblasts. The myofibroblast phenotype is characterized by ␣-smooth muscle actin expression (28). Myofibroblasts appear to be responsible for matrix deposition during wound healing (31). In the adult lung, elastin mRNA levels can be modulated by effector substances released from macrophages or resident interstitial cells or from the extracellular matrix after proteolytic injury. Elastin mRNA can be upregulated by insulin-like growth factor, transforming growth factor (TGF)-, and retinoic acid (13,16,22) and downregulated by basic fibroblast growth factor (7) and interleukin (IL)-1 (3).IL-1 affects gene transcription via several different families of trans-acting factors including AP-1 proteins, nuclear factor (NF)/IL-6-related factors [CCAAT box/enhancer b...
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