Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent

Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4+ and γδ+ T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a−/− mice confirmed an essential role for IL-17A. Mechanistically, using ifnγ−/−, il10−/−, il10−/−il12p40−/−, and il10−/−il17a−/− mice and TGF-β blockade, we demonstrate that IL-17A–driven fibrosis is suppressed by IL-10 and facilitated by IFN-γ and IL-12/23p40. BLM-induced IL-17A production was also TGF-β dependent, and recombinant IL-17A–mediated fibrosis required TGF-β, suggesting cooperative roles for IL-17A and TGF-β in the development of fibrosis. Finally, we show that fibrosis induced by IL-1β, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1β were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis.

Download Full-text

IL-12 attenuates bleomycin-induced pulmonary fibrosis

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.281.1.l92 ◽

2001 ◽

Vol 281 (1) ◽

pp. L92-L97 ◽

Cited By ~ 72

Author(s):

Michael P. Keane ◽

John A. Belperio ◽

Marie D. Burdick ◽

Robert M. Strieter

Keyword(s):

Pulmonary Fibrosis ◽

Bronchoalveolar Lavage ◽

Intraperitoneal Injection ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Time Dependent ◽

Simultaneous Administration ◽

Potent Inducer ◽

Ifn Γ ◽

Daily Intraperitoneal Injection

Interleukin (IL)-12 is a potent inducer of interferon (IFN)-γ. We postulated that IL-12 would attenuate bleomycin-induced pulmonary fibrosis. To test this hypothesis, we administered IL-12 or murine serum albumin to bleomycin-treated mice by daily intraperitoneal injection until day 12. Mice treated with IL-12 demonstrated decreased hydroxyproline levels compared with control treated mice. Furthermore, administration of IL-12 led to a time-dependent increase in both lung and bronchoalveolar lavage fluid IFN-γ. The antifibrotic effect of IL-12 could be attenuated with simultaneous administration of neutralizing anti-IFN-γ antibodies. These findings support the notion that IL-12 attenuates bleomycin-induced pulmonary fibrosis via modulation of IFN-γ production.

Download Full-text

Overexpression Of Matrix Metalloproteinases In Bronchoalveolar Lavage Fluid (BALF) And Lung Tissue Of Non-Small Cell Lung Cancer (NSCLC) Patients: Comparison With Idiopathic Pulmonary Fibrosis (IPF)

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a4427 ◽

2012 ◽

Author(s):

Katerina D. Samara ◽

Konstantinos Karagiannis ◽

Ismini Lasithiotaki ◽

Irini Lambiri ◽

Nikolaos M. Siafakas ◽

...

Keyword(s):

Lung Cancer ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Bronchoalveolar Lavage ◽

Small Cell Lung Cancer ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Small Cell ◽

Small Cell Lung ◽

Nsclc Patients

Download Full-text

Evaluation of LBM415 (NVP PDF-713), a Novel Peptide Deformylase Inhibitor, for Treatment of Experimental Mycoplasma pneumoniae Pneumonia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.10.4128-4136.2005 ◽

2005 ◽

Vol 49 (10) ◽

pp. 4128-4136 ◽

Cited By ~ 16

Author(s):

Monica Fonseca-Aten ◽

Christine M. Salvatore ◽

Asunción Mejías ◽

Ana M. Ríos ◽

Susana Chávez-Bueno ◽

...

Keyword(s):

Bronchoalveolar Lavage ◽

Mycoplasma Pneumoniae ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Placebo Treatment ◽

Community Acquired Pneumonia ◽

Peptide Deformylase ◽

Necrosis Factor Alpha ◽

Days Of Therapy ◽

Ifn Γ

ABSTRACT Mycoplasma pneumoniae is a major cause of community-acquired pneumonia. We evaluated the efficacy of LBM415, a novel peptide deformylase inhibitor antimicrobial agent, for the treatment of M. pneumoniae pneumonia in a mouse model. Eight-week-old BALB/c mice were intranasally inoculated once with 107 CFU of M. pneumoniae. Groups of mice were treated with LBM415 (50 mg/kg of body weight) or placebo subcutaneously daily for 13 days, starting 24 h after inoculation. Groups of mice were evaluated at the baseline; at days of treatment 1, 3, 6, and 13; and at 7 days after treatment. The MIC of LBM415 against M. pneumoniae was <0.005 μg/ml. LBM415-treated mice had significantly lower bronchoalveolar lavage fluid M. pneumoniae concentrations than placebo-treated mice on days 6 and 13 of treatment. Compared with placebo treatment, therapy with LBM415 significantly decreased lung histopathology scores at days 3, 6, and 13 of treatment and at 7 days after treatment. Airway obstruction was significantly lower in LBM415-treated mice than in placebo-treated mice on days 1, 3, and 6 of treatment and after 7 days of therapy, while airway hyperresponsiveness was significantly lower only on day 3 of therapy. The bronchoalveolar lavage fluid concentrations of tumor necrosis factor alpha, gamma interferon (IFN-γ), interleukin-6 (IL-6), IL-12, KC (functional IL-8), monocyte chemotactic protein 1, macrophage inflammatory protein 1α, monokine induced by IFN-γ, and IFN-inducible protein 10 were significantly reduced in LBM415-treated mice compared with the levels in placebo-treated mice. There were no differences in the bronchoalveolar lavage fluid concentrations of granulocyte-macrophage colony-stimulating factor, IL-1β, IL-2, IL-4, IL-5, and IL-10 between the two groups of mice. LBM415 therapy had beneficial microbiologic, histologic, respiratory, and immunologic effects on acute murine M. pneumoniae pneumonia.

Download Full-text

Cytokine profile of bronchoalveolar lavage fluid in patients with combined pulmonary fibrosis and emphysema

Respirology ◽

10.1111/j.1440-1843.2012.02182.x ◽

2012 ◽

Vol 17 (5) ◽

pp. 814-820 ◽

Cited By ~ 22

Author(s):

SADATOMO TASAKA ◽

KOSUKE MIZOGUCHI ◽

YOHEI FUNATSU ◽

HO NAMKOONG ◽

WAKAKO YAMASAWA ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Bronchoalveolar Lavage ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Cytokine Profile

Download Full-text

Hyaluronan and procollagen type III aminoterminal peptide in serum and bronchoalveolar lavage fluid from patients with pulmonary fibrosis

Apmis ◽

10.1111/j.1699-0463.1995.tb01433.x ◽

1995 ◽

Vol 103 (7-8) ◽

pp. 749-754 ◽

Cited By ~ 7

Author(s):

N. MILMAN ◽

M. S. KRISTENSEN ◽

K. BENTSEN

Keyword(s):

Pulmonary Fibrosis ◽

Bronchoalveolar Lavage ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Type Iii ◽

Procollagen Type

Download Full-text

Syndecan-4 Inhibits the Development of Pulmonary Fibrosis by Attenuating TGF-β Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms20204989 ◽

2019 ◽

Vol 20 (20) ◽

pp. 4989 ◽

Cited By ~ 4

Author(s):

Yoshinori Tanino ◽

Xintao Wang ◽

Takefumi Nikaido ◽

Kenichi Misa ◽

Yuki Sato ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Heparan Sulfate ◽

Bronchoalveolar Lavage Fluid ◽

Pulmonary Inflammation ◽

Lavage Fluid ◽

Lung Fibroblasts ◽

Fibrosis Score ◽

Wild Type ◽

Deficient Mice

Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4′s critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and α-smooth muscle action (α-SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-β expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-β-induced Smad3 activation, collagen and α-SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-β-induced Smad3 activation and upregulated collagen and α-SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-β signaling.

Download Full-text

Paeonol attenuates airway inflammation and hyperresponsiveness in a murine model of ovalbumin-induced asthma

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y10-077 ◽

2010 ◽

Vol 88 (10) ◽

pp. 1010-1016 ◽

Cited By ~ 20

Author(s):

Qiang Du ◽

Gan-Zhu Feng ◽

Li Shen ◽

Jin Cui ◽

Jian-Kang Cai

Keyword(s):

Bronchoalveolar Lavage ◽

Airway Inflammation ◽

Bronchoalveolar Lavage Fluid ◽

Immunoglobulin E ◽

Therapeutic Potential ◽

Lavage Fluid ◽

Interleukin 4 ◽

Moutan Cortex ◽

Ifn Γ ◽

Anti Inflammatory

Paeonol, the main active component isolated from Moutan Cortex, possesses extensive pharmacological activities such as anti-inflammatory, anti-allergic, and immunoregulatory effects. In the present study, we examined the effects of paeonol on airway inflammation and hyperresponsiveness in a mouse model of allergic asthma. BALB/c mice sensitized and challenged with ovalbumin were administered paeonol intragastrically at a dose of 100 mg/kg daily. Paeonol significantly suppressed ovalbumin-induced airway hyperresponsiveness to acetylcholine chloride. Paeonol administration significantly inhibited the total inflammatory cell and eosinophil count in bronchoalveolar lavage fluid. Treatment with paeonol significantly enhanced IFN-γ levels and decreased interleukin-4 and interleukin-13 levels in bronchoalveolar lavage fluid and total immunoglobulin E levels in serum. Histological examination of lung tissue demonstrated that paeonol significantly attenuated allergen-induced lung eosinophilic inflammation and mucus-producing goblet cells in the airway. These data suggest that paeonol exhibits anti-inflammatory activity in allergic mice and may possess new therapeutic potential for the treatment of allergic bronchial asthma.

Download Full-text