leptin and Pulmonary-Fibrosis

Asthma patients with comorbid obesity exhibit increased disease severity, in part, due to airway remodeling, which is also observed in mouse models of asthma and obesity. A mediator of remodeling that is increased in obesity is leptin. We hypothesized that in a mouse model of allergic airways disease, mice receiving exogenous leptin would display increased airway inflammation and fibrosis.. Five-week-old male and female C57BL/6J mice were challenged with intranasal house dust mite (HDM) allergen or saline 5 days per week for 6 weeks (n = 6-9 per sex, per group). Following each HDM exposure, mice received subcutaneous recombinant human leptin or saline. At 48 h after the final HDM challenge, lung mechanics were evaluated and the mice were sacrificed. Bronchoalveolar lavage was performed and differential cell counts were determined. Lung tissue was stained with Masson's trichrome, periodic acid-Schiff, and hematoxylin and eosin stains. Mouse lung fibroblasts were cultured, and whole lung mRNA was isolated.. Leptin did not affect mouse body weight, but HDM+leptin increased baseline blood glucose. In mixed-sex groups, leptin increased mouse lung fibroblast invasiveness and increased lung Col1a1 mRNA expression. Total lung resistance and tissue damping were increased with HDM+leptin treatment, but not leptin or HDM alone. Female mice exhibited enhanced airway responsiveness to methacholine with HDM+leptin treatment, while leptin alone decreased total respiratory system resistance in male mice.. In HDM-induced allergic airways disease, administration of exogenous leptin to mice enhanced lung resistance and increased markers of fibrosis, with differing effects between males and females.

Topics: Allergens; Animals; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Fibrosis; Humans; Hypersensitivity; Leptin; Lung; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Obesity; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Pyroglyphidae; RNA, Messenger

Leptin, a protein-related product of the obesity gene, plays an important role in the pathogenesis of fibrotic diseases including pulmonary fibrosis. As a highly conservative process, autophagy regulates various biological functions. Otherwise, insufficient autophagy has been described in alveolar epithelial cells (AEC) to cope with the progression of pulmonary fibrosis. Hence, this study is to investigate the effects of leptin on fibrosis in TGF-β1 induced epithelial mesenchymal transition (EMT) and the potential roles of autophagy in this processes. Our results showed that the elevated leptin level in serum correlated with the severity of lung fibrosis and leptin significantly promoted the EMT in A549 cells as evidenced by promoting collagen I and α-SMA production. Additionally, treatment with leptin decreased autophagosome formation, inhibited the lipidation of LC3I to LC3II, and up-regulated the expression of p62 via activating PI3K/Akt/mTOR pathway, which is indicative of inhibition of autophagy by leptin. Finally, rapmycin pretreatment reversed the pro-fibrogenic effects of leptin. Taken together, our study suggested that leptin accelerated the EMT of A549 cells through inhibiting autophagy via PI3K/Akt/mTOR pathway.

Topics: A549 Cells; Adult; Autophagy; Epithelial-Mesenchymal Transition; Humans; Leptin; Lung; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis; Signal Transduction; TOR Serine-Threonine Kinases

Obese patients with asthma respond poorly to conventional asthma medications, resulting in severe symptoms and poor prognosis. Roflumilast, a phosphodiesterase-4 inhibitor that lowers the levels of various substances that are implicated in obese subjects with asthma, may be effective in the treatment of those subjects. We evaluated the potential of roflumilast as a novel therapeutic agent for obese subjects with asthma. We designed three models: diet-induced obesity (DIO); DIO with ovalbumin (OVA); and OVA. We fed C57BL/6J mice a high-fat diet for 3 months with or without OVA sensitization and challenge. Roflumilast or dexamethasone was administered orally three times at 2-day intervals in the last experimental week. Airway hyperresponsiveness resulting from DIO significantly improved in the roflumilast-treated group compared with the dexamethasone-treated groups. Although DIO did not affect the cell proliferation in bronchoalveolar lavage fluid, increased fibrosis was seen in the DIO group, which significantly improved from treatment with roflumilast. DIO-induced changes in adiponectin and leptin levels were improved by roflumilast, whereas dexamethasone aggravated them. mRNA levels and proteins of TNF-α, transforming growth factor-β, IL-1β, and IFN-γ increased in the DIO group and decreased with roflumilast. The reactive oxygen species levels were also increased in the DIO group and decreased by roflumilast. In the DIO plus OVA and OVA models, roflumilast improved Th1 and Th2 cell activation to a greater extent than dexamethasone. Roflumilast is significantly more effective than dexamethasone against airway hyperresponsiveness caused by DIO in the murine model. Roflumilast may represent a promising therapeutic agent for the treatment of obese patients with asthma.

Topics: Adiponectin; Aminopyridines; Animals; Benzamides; Cell Proliferation; Cyclopropanes; Cytokines; Diet; Disease Models, Animal; Leptin; Mice, Inbred C57BL; Models, Biological; Obesity; Ovalbumin; Pulmonary Fibrosis; Reactive Oxygen Species; Respiratory Hypersensitivity; T-Lymphocytes

To observe the expression of leptin (LP) and its influence on pulmonary fibrosis in experimental rats with silicosis and the correlation between the expressions of leptin and HIF-1α.. A total of 120 male Sprague-Dawley rats were randomly divided into normal control group, silicosis model group, LP intervention groups (consisting of LP5, LP10 and LP20 groups according to the concentration of LP). The rats in the normal control group were intratracheally administered 1 mL normal sodium, and the ones in the other groups were intratracheally given 1 mL SiO₂(40 mg/mL) suspension. The rats in LP intervention groups were intraperitoneally injected with leptin 5, 10, 20 ng/kg.d respectively from the first day. Six rats in each group were sacrificed on the 7th, 14th, 21th and 28th day. The expression of LP on the 7th, 14th, 21th and 28th day and the hydroxyproline content on the 28th day in rat lung tissues were measured by ELISA, and the expressions of HIF-1α and LP proteins in the lung tissues of the silicosis model group were measured by Western blotting.. There were significant differences in the expression of LP in the lung tissues at each time point (7th, 14th, 21th and 28th day) among the five groups (F=669.18, 948.67, 1 172.00, 521.55, P<0.05). The LP content in the silicosis model group was significantly higher than that in the normal control group (P<0.05) and the expression of LP in the LP intervention groups were significantly elevated at each time point (P<0.05) as compared with the silicosis model group. Hydroxyproline content on 28th day was (0.89 ± 0.16), (3.14 ± 0.40), (3.78 ± 0.27), (4.35 ± 0.13), (4.87 ± 0.16) mg/g in normal control group, silicosis model group, LP5, LP10 and LP20 intervention groups, respectively. Compared with the normal control group, hydroxyproline content in the silicosis model group significantly increased (P<0.05), and compared with the silicosis model group, hydroxyproline content in LP intervention groups were significantly raised (P<0.05). The significant positive correlations were noted between the expressions of HIF-1α and LP (r=0.876, 0.796, 0.859 and 0.854 at each time, P<0.05).. The expression of LP goes up significantly in the lung tissues of rats with silicosis. Addition of exogenous leptin can increase the collagen deposition in the lung tissues; meanwhile leptin has a positive correlation with HIF-1α.

Topics: Animals; Blotting, Western; Collagen; Enzyme-Linked Immunosorbent Assay; Hydroxyproline; Hypoxia-Inducible Factor 1, alpha Subunit; Injections, Intraperitoneal; Leptin; Lung; Male; Pulmonary Fibrosis; Random Allocation; Rats; Rats, Sprague-Dawley; Silicosis; Time Factors

Topics: Animals; Humans; Leptin; Mice; Pulmonary Fibrosis; Respiratory Distress Syndrome