Age-Dependent Chronic Lung Injury and Pulmonary Fibrosis following Single Exposure to Hydrochloric Acid

Exposure to hydrochloric acid (HCl) represents a threat to public health. Children may inhale higher doses and develop greater injury because of their smaller airways and faster respiratory rate. We have developed a mouse model of pediatric exposure to HCl by intratracheally instilling p24 mice (mice 24 days old; 8–10 g) with 2 µL/g 0.1 N HCl, and compared the profile of lung injury to that in HCl-instilled adults (10 weeks old; 25–30 g) and their age-matched saline controls. After 30 days, alveolar inflammation was observed with increased proteinosis and mononuclear cells in the bronchoalveolar lavage fluid (BALF) in both HCl-instilled groups. Young p24 animals—but not adults—exhibited higher NLR family pyrin domain containing 3 (NLRP3) inflammasome levels. Increased amounts of Transforming Growth Factor-β (TGF-β) mRNA and its intracellular canonical and non-canonical pathways (p-Smad2 and p-ERK) were found in the lungs of both young and adult HCl-instilled mice. Constitutive age-related differences were observed in the levels of heat shock protein family (HSP70 and HSP90). HCl equally provoked the deposition of collagen and fibronectin; however, significant age-dependent differences were observed in the increase in elastin and tenascin C mRNA. HCl induced pulmonary fibrosis with an increased Ashcroft score, which was higher in adults, and a reduction in alveolar Mean Alveolar Linear Intercept (MALI). Young mice developed increased Newtonian resistance (Rn) and lower PV loops, while adults showed a higher respiratory system resistance and elastance. This data indicate that young p24 mice can suffer long-term complications from a single exposure to HCl, and can develop chronic lung injury characterized by a stronger persistent inflammation and lesser fibrotic pattern, mostly in the airways, differently from adults. Further data are required to characterize HCl time- and dose-dependent injury in young animals and to identify new key-molecular targets.

Download Full-text

Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis?

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00489.2001 ◽

2002 ◽

Vol 283 (1) ◽

pp. L1-L11 ◽

Cited By ~ 26

Author(s):

Margaret K. Winkler ◽

John L. Fowlkes

Keyword(s):

Acute Lung Injury ◽

Growth Factors ◽

Growth Factor ◽

Pulmonary Fibrosis ◽

Lung Injury ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Inflammatory Cells ◽

Transforming Growth Factor Β ◽

Target Cells

Chronic lung disease due to interstitial fibrosis can be a consequence of acute lung injury and inflammation. The inflammatory response is mediated through the migration of inflammatory cells, actions of proinflammatory cytokines, and the secretion of matrix-degrading proteinases. After the initial inflammatory insult, successful healing of the lung may occur, or alternatively, dysregulated tissue repair can result in scarring and fibrosis. On the basis of recent insights into the mechanisms underlying acute lung injury and its long-term consequences, data suggest that proteinases, such as the matrix metalloproteinases (MMPs), may not only be involved in the breakdown and remodeling that occurs during the injury but may also cause the release of growth factors and cytokines known to influence growth and differentiation of target cells within the lung. Through the release of and activation of fibrosis-promoting cytokines and growth factors such as transforming growth factor-β1, tumor necrosis factor-α, and insulin-like growth factors by MMPs, we propose that these metalloproteinases may be integral to the initiation and progression of pulmonary fibrosis.

Download Full-text

Expression of mutant human epidermal receptor 3 attenuates lung fibrosis and improves survival in mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.01360.2004 ◽

2005 ◽

Vol 99 (1) ◽

pp. 298-307 ◽

Cited By ~ 20

Author(s):

David E. Nethery ◽

Bethany B. Moore ◽

George Minowada ◽

James Carroll ◽

Jihane A. Faress ◽

...

Keyword(s):

Growth Factor ◽

Lung Injury ◽

Transgenic Mice ◽

Bronchoalveolar Lavage ◽

Bronchoalveolar Lavage Fluid ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Lavage Fluid ◽

Dominant Negative ◽

Nontransgenic Littermate

Neuregulin-1 (NRG-1), binding to the human epidermal growth factor receptor HER2/HER3, plays a role in pulmonary epithelial cell proliferation and recovery from injury in vitro. We hypothesized that activation of HER2/HER3 by NRG-1 would also play a role in recovery from in vivo lung injury. We tested this hypothesis using bleomycin lung injury of transgenic mice incapable of signaling through HER2/HER3 due to lung-specific dominant-negative HER3 (DNHER3) expression. In animals expressing DNHER3, protein leak, cell infiltration, and NRG-1 levels in bronchoalveolar lavage fluid increased after injury, similar to that in nontransgenic littermate control animals. However, HER2/HER3 was not activated, and DNHER3 animals displayed fewer lung morphological changes at 10 and 21 days after injury ( P = 0.01). In addition, they contained 51% less collagen in injured lungs ( P = 0.04). Transforming growth factor-β1 did not increase in bronchoalveolar lavage fluid from DNHER3 mice compared with nontransgenic littermate mice ( P = 0.001), suggesting that a mechanism for the decreased fibrosis was lack of transforming growth factor-β1 induction in DNHER3 mice. Severe lung injury (0.08 units bleomycin) resulted in 80% mortality of nontransgenic mice, but only 35% mortality of DNHER3 transgenic mice ( P = 0.04). Thus inhibition of HER2/HER3 signaling protects against pulmonary fibrosis and improves survival.

Download Full-text

Myeloid Fbxw7 Prevents Pulmonary Fibrosis by Suppressing TGF-β Production

Frontiers in Immunology ◽

10.3389/fimmu.2021.760138 ◽

2022 ◽

Vol 12 ◽

Author(s):

Jia He ◽

Yue Du ◽

Gaopeng Li ◽

Peng Xiao ◽

Xingzheng Sun ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Mononuclear Cells ◽

Transforming Growth Factor ◽

Treatment Options ◽

Myeloid Cell ◽

Transforming Growth Factor Β ◽

Peripheral Blood Mononuclear ◽

Regulation Mechanisms ◽

Insight Into

Idiopathic pulmonary fibrosis (IPF) is a group of chronic interstitial pulmonary diseases characterized by an inexorable decline in lung function with limited treatment options. The abnormal expression of transforming growth factor-β (TGF-β) in profibrotic macrophages is linked to severe pulmonary fibrosis, but the regulation mechanisms of TGF-β expression are incompletely understood. We found that decreased expression of E3 ubiquitin ligase Fbxw7 in peripheral blood mononuclear cells (PBMCs) was significantly related to the severity of pulmonary fibrosis in IPF patients. Fbxw7 is identified to be a crucial suppressing factor for pulmonary fibrosis development and progression in a mouse model induced by intratracheal bleomycin treatment. Myeloid cell-specific Fbxw7 deletion increases pulmonary monocyte-macrophages accumulation in lung tissue, and eventually promotes bleomycin-induced collagen deposition and progressive pulmonary fibrosis. Notably, the expression of TGF-β in profibrotic macrophages was significantly upregulated in myeloid cell-specific Fbxw7 deletion mice after bleomycin treatment. C-Jun has long been regarded as a critical transcription factor of Tgfb1, we clarified that Fbxw7 inhibits the expression of TGF-β in profibrotic macrophages by interacting with c-Jun and mediating its K48-linked ubiquitination and degradation. These findings provide insight into the role of Fbxw7 in the regulation of macrophages during the pathogenesis of pulmonary fibrosis.

Download Full-text

Age-Related Alterations in Signaling Pathways in Articular Chondrocytes: Implications for the Pathogenesis and Progression of Osteoarthritis - A Mini-Review

Gerontology ◽

10.1159/000448711 ◽

2016 ◽

Vol 63 (1) ◽

pp. 29-35 ◽

Cited By ~ 22

Author(s):

Peter van der Kraan ◽

Csaba Matta ◽

Ali Mobasheri

Keyword(s):

Signaling Pathways ◽

Transforming Growth Factor ◽

Articular Chondrocytes ◽

Musculoskeletal Diseases ◽

Indirect Costs ◽

Transforming Growth Factor Β ◽

Joint Disease ◽

Age Related ◽

Age Dependent ◽

Care Systems

Musculoskeletal conditions are a major burden on individuals, healthcare systems, and social care systems throughout the world, with indirect costs having a predominant economic impact. Aging is a major contributing factor to the development and progression of arthritic and musculoskeletal diseases. Indeed, aging and inflammation (often referred to as ‘inflammaging') are critical risk factors for the development of osteoarthritis (OA), which is one of the most common forms of joint disease. The term ‘chondrosenescence' has recently been introduced to define the age-dependent deterioration of chondrocyte function and how it undermines cartilage function in OA. An important component of chondrosenescence is the age-related deregulation of subcellular signaling pathways in chondrocytes. This mini-review discusses the role of age-related alterations in chondrocyte signaling pathways. We focus our attention on two major areas: age-dependent alterations in transforming growth factor-β signaling and changes in protein kinase and phosphoprotein phosphatase activities in aging chondrocytes. A better understanding of the basic signaling mechanisms underlying aging in chondrocytes is likely to facilitate the development of new therapeutic and preventive strategies for OA and a range of other age-related osteoarticular disorders.

Download Full-text

Attenuated pulmonary fibrosis in sialidase-3 knockout (Neu3−/−) mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00275.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. L165-L179 ◽

Cited By ~ 5

Author(s):

Tejas R. Karhadkar ◽

Wensheng Chen ◽

Richard H. Gomer

Keyword(s):

Pulmonary Fibrosis ◽

Mononuclear Cells ◽

Transforming Growth Factor ◽

Human Peripheral Blood ◽

Lavage Fluid ◽

Scar Tissue ◽

Transforming Growth Factor Β1 ◽

Peripheral Blood Mononuclear ◽

Male And Female

Pulmonary fibrosis involves the formation of inappropriate scar tissue in the lungs, but what drives fibrosis is unclear. Sialidases (also called neuraminidases) cleave terminal sialic acids from glycoconjugates. In humans and mice, pulmonary fibrosis is associated with desialylation of glycoconjugates and upregulation of sialidases. Of the four mammalian sialidases, we previously detected only NEU3 in the bronchoalveolar lavage fluid from mice with bleomycin-induced pulmonary fibrosis. In this report, we show that NEU3 upregulates extracellular accumulation of the profibrotic cytokines IL-6 and IL-1β, and IL-6 upregulates NEU3 in human peripheral blood mononuclear cells, suggesting that NEU3 may be part of a positive feedback loop potentiating fibrosis. To further elucidate the role of NEU3 in fibrosis, we used bleomycin to induce lung fibrosis in wild-type C57BL/6 and Neu3−/− mice. At 21 days after bleomycin, compared with male and female C57BL/6 mice, male and female Neu3−/− mice had significantly less inflammation, less upregulation of other sialidases and the profibrotic cytokine active transforming growth factor β1, and less fibrosis in the lungs. Our results suggest that NEU3 participates in fibrosis and that NEU3 could be a target to develop treatments for fibrosis.

Download Full-text

Ganoderic Acid A Inhibits Bleomycin-Induced Lung Fibrosis in Mice

Pharmacology ◽

10.1159/000505297 ◽

2020 ◽

Vol 105 (9-10) ◽

pp. 568-575

Author(s):

Gaoyan Wen ◽

Tian Li ◽

Hua He ◽

Xianmei Zhou ◽

Jia Zhu

Keyword(s):

Pulmonary Fibrosis ◽

Lung Injury ◽

Protective Effect ◽

Transforming Growth Factor ◽

Dry Weight ◽

Transforming Growth Factor Β ◽

Enzyme Linked Immunosorbent Assay ◽

Protective Effects ◽

Ganoderic Acid ◽

Tnf Α

Background: To study the protective effects of ganoderic acid A (GAA) on bleomycin (BLM)-induced pulmonary fibrosis. Methods: ICR mice were intratracheally instilled with BLM to induce pulmonary fibrosis on day 0. Then the mice were orally given GAA (25, 50 mg/kg) or dexamethasone (2 mg/kg). After treatment for 21 days, the mice were sacrificed. Wet dry weight (W/D) ratio of lung was used to detect pulmonary edema. Myeloperoxidase (MPO), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), and superoxide dismutase (SOD) were detected by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining was used to evaluate the pathological changes. The levels of transforming growth factor β (TGF-β), phosphorylated-smad3 (p-smad3), p-IκB, and p-nuclear factor-kappa B (NF-κB) in lung tissue were detected by western blot. Results: GAA treatment significantly improved MPO activity, W/D ratio, and lung histopathology. The protective effect of GAA may be related to downregulation of TNF-α, IL-1β, IL-6, MDA and upregulation of SOD. In addition, GAA significantly decreased the levels of TGF-β, p-smad3, p-IκB, and p-NF-κB, compared with those in BLM group. Conclusion: GAA has protective effect on BLM-induced lung injury, and TGF-β/Smad-3/NF-κB signaling pathway may play an important role in the pathogenesis of BLM-induced lung injury.

Download Full-text

Ecto-5′-nucleotidase CD73 modulates the innate immune response to influenza infection but is not required for development of influenza-induced acute lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00130.2015 ◽

2015 ◽

Vol 309 (11) ◽

pp. L1313-L1322 ◽

Cited By ~ 15

Author(s):

Famke Aeffner ◽

Parker S. Woods ◽

Ian C. Davis

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Pulmonary Edema ◽

Influenza A ◽

Transforming Growth Factor ◽

Influenza Infection ◽

Transforming Growth Factor Β ◽

Lavage Fluid ◽

Extracellular Nucleotides ◽

Normal Lung

Extracellular nucleotides and nucleosides are important signaling molecules in the lung. Nucleotide and nucleoside concentrations in alveolar lining fluid are controlled by a complex network of surface ectonucleotidases. Previously, we demonstrated that influenza A/WSN/33 (H1N1) virus resulted in increased levels of the nucleotide ATP and the nucleoside adenosine in bronchoalveolar lavage fluid (BALF) of wild-type (WT) C57BL/6 mice. Influenza-induced acute lung injury (ALI) was highly attenuated in A1-adenosine receptor-knockout mice. Because AMP hydrolysis by the ecto-5′-nucleotidase (CD73) plays a central role in and is rate-limiting for generation of adenosine in the normal lung, we hypothesized that ALI would be attenuated in C57BL/6-congenic CD73-knockout (CD73-KO) mice. Infection-induced hypoxemia, bradycardia, viral replication, and bronchoconstriction were moderately increased in CD73-KO mice relative to WT controls. However, postinfection weight loss, pulmonary edema, and parenchymal dysfunction were not altered. Treatment of WT mice with the CD73 inhibitor 5'-(α,β-methylene) diphosphate (APCP) also had no effect on infection-induced pulmonary edema but modestly attenuated hypoxemia. BALF from CD73-KO and APCP-treated WT mice contained more IL-6 and CXCL-10/IFN-γ-induced protein 10, less CXCL-1/keratinocyte chemoattractant, and fewer neutrophils than BALF from untreated WT controls. BALF from APCP-treated WT mice also contained fewer alveolar macrophages and more transforming growth factor-β than BALF from untreated WT mice. These results indicate that CD73 is not necessary for development of ALI following influenza A virus infection and suggest that tissue-nonspecific alkaline phosphatase may be responsible for increased adenosine generation in the infected lung. However, they do suggest that CD73 has a previously unrecognized immunomodulatory role in influenza.

Download Full-text

Sex-Related Differences in Murine Models of Chemically Induced Pulmonary Fibrosis

International Journal of Molecular Sciences ◽

10.3390/ijms22115909 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5909

Author(s):

Pavel Solopov ◽

Ruben Manuel Luciano Colunga Biancatelli ◽

Christiana Dimitropoulou ◽

John D. Catravas

Keyword(s):

Pulmonary Fibrosis ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Heat Shock Protein 90 ◽

Transforming Growth Factor Β ◽

Lavage Fluid ◽

Total Protein Content ◽

Female Mice ◽

Downstream Signaling ◽

Chemically Induced

We developed two models of chemically induced chronic lung injury and pulmonary fibrosis in mice (intratracheally administered hydrochloric acid (HCl) and intratracheally administered nitrogen mustard (NM)) and investigated male–female differences. Female mice exhibited higher 30-day survival and less weight loss than male mice. Thirty days after the instillation of either HCl or NM, bronchoalveolar lavage fluid displayed a persistent, mild inflammatory response, but with higher white blood cell numbers and total protein content in males vs. females. Furthermore, females exhibited less collagen deposition, milder pulmonary fibrosis, and lower Ashcroft scores. After instillation of either HCl or NM, all animals displayed increased values of phosphorylated (activated) Heat Shock Protein 90, which plays a crucial role in the alveolar wound-healing processes; however, females presented lower activation of both transforming growth factor-β (TGF-β) signaling pathways: ERK and SMAD. We propose that female mice are protected from chronic complications of a single exposure to either HCl or NM through a lesser activation of TGF-β and downstream signaling. The understanding of the molecular mechanisms that confer a protective effect in females could help develop new, gender-specific therapeutics for IPF.

Download Full-text

Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Inhibitor as a Novel Therapeutic Tool for Lung Injury

International Journal of Molecular Sciences ◽

10.3390/ijms21207761 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7761

Author(s):

Roberta Fusco ◽

Rosalba Siracusa ◽

Ramona D’Amico ◽

Marika Cordaro ◽

Tiziana Genovese ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Transforming Growth Factor ◽

Tissue Injury ◽

Body Weight Gain ◽

Smooth Muscle Actin ◽

Immunohistochemical Analysis ◽

Inflammatory Cells ◽

Transforming Growth Factor Β ◽

Lavage Fluid ◽

Immunomodulatory Activity

Pulmonary fibrosis is a progressive disease characterized by lung remodeling due to excessive deposition of extracellular matrix. In this study, the bleomycin experimental model of pulmonary fibrosis was employed to investigate the anti-fibrotic and immunomodulatory activity of the inhibition of MALT1 protease activity. Mice received a single intra-tracheal administration of bleomycin (1 mg/kg) in the presence or absence of MI-2, a selective MALT1 inhibitor, (a dose of 30 mg/kg administered intra-peritoneally 1 h after bleomycin and daily until the end of the experiment). Seven days after bleomycin instillation mice were sacrificed and bronchoalveolar lavage fluid analysis, measurement of collagen content in the lung, histology, molecular analysis and immunohistochemistry were performed. To evaluate mortality and body weight gain a subset of mice was administered daily with MI-2 for 21 days. Mice that received MI-2 showed decreased weight loss and mortality, inflammatory cells infiltration, cytokines overexpression and tissue injury. Moreover, biochemical and immunohistochemical analysis displayed that MI-2 was able to modulate the excessive production of reactive oxygen species and the inflammatory mediator upregulation induced by bleomycin instillation. Additionally, MI-2 demonstrated anti-fibrotic activity by reducing transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA) and receptor associated factor 6 (TRAF6) expression. The underlying mechanisms for the protective effect of MI-2 bleomycin induced pulmonary fibrosis may be attributed to its inhibition on NF-κB pathway. This is the first report showing the therapeutic role of MALT1 inhibition in a bleomycin model of pulmonary fibrosis, thus supporting further preclinical and clinical studies.

Download Full-text

Age-driven developmental drift in the pathogenesis of idiopathic pulmonary fibrosis

European Respiratory Journal ◽

10.1183/13993003.00398-2016 ◽

2016 ◽

Vol 48 (2) ◽

pp. 538-552 ◽

Cited By ~ 50

Author(s):

Moisés Selman ◽

Carlos López-Otín ◽

Annie Pardo

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Alveolar Epithelial Cells ◽

Cell Behaviour ◽

Alveolar Epithelial ◽

Similar Expression Profile ◽

Age Related ◽

Developmental Signalling

Idiopathic pulmonary fibrosis (IPF) is a progressive and usually lethal disease of unknown aetiology. A growing body of evidence supports that IPF represents an epithelial-driven process characterised by aberrant epithelial cell behaviour, fibroblast/myofibroblast activation and excessive accumulation of extracellular matrix with the subsequent destruction of the lung architecture. The mechanisms involved in the abnormal hyper-activation of the epithelium are unclear, but we propose that recapitulation of pathways and processes critical to embryological development associated with a tissue specific age-related stochastic epigenetic drift may be implicated. These pathways may also contribute to the distinctive behaviour of IPF fibroblasts. Genomic and epigenomic studies have revealed that wingless/Int, sonic hedgehog and other developmental signalling pathways are reactivated and deregulated in IPF. Moreover, some of these pathways cross-talk with transforming growth factor-β activating a profibrotic feedback loop. The expression pattern of microRNAs is also dysregulated in IPF and exhibits a similar expression profile to embryonic lungs. In addition, senescence, a process usually associated with ageing, which occurs early in alveolar epithelial cells of IPF lungs, likely represents a conserved programmed developmental mechanism. Here, we review the major developmental pathways that get twisted in IPF, and discuss the connection with ageing and potential therapeutic approaches.

Download Full-text