Inhibition of mesenchymal stromal cells’ chemotactic effect to ameliorate paraquat-induced pulmonary fibrosis

Hongliang Zhang, Bing Xiao, Li Jiang, Wei Yao, Huahao Shen, Xudong Xiang

    Research output: Contribution to journalArticle

    Abstract

    Background: Paraquat (PQ) poisoning is one of the leading causes of suicide attempts in China signature by acute onset of respiratory distress with massive matrix production resulting in progressive pulmonary fibrosis. There is no specific antidote and mortality remains high without effective treatment available. The cellular mechanisms underlying PQ-induced pulmonary fibrosis remain largely unknown. Objectives: To determine the origin of mesenchymal stem cells (MSCs) migrated to the lung after PQ exposure and their roles in PQ-induced pulmonary fibrosis, to further explore the possible mechanisms involved in these processes, and to help finding novel therapies. Methods: We used a combination of lineage tracking techniques to investigate the contributions of several cells of MSCs, marked by Nestin or CXCL12, and traced their co-expression of α-smooth muscle actin (α-SMA), a marker for fibrosis, or their co-location with matrix production, marked by collagen-1 production (Col1-GFP) following PQ exposure. Then, we used a CXCL12flox/flox; Prx1-Cre mice and a pharmacologic agent AMD3100 to selectively deplete chemotactic mechanism of the MSCs, and tested pro-fibrotic pathways, fibrotic processes and survival of mice after PQ exposure. Results: Our results showed that after paraquat exposure, the residential Nestin + MSCs were quickly expanded and contributed to extracellular matrix production. Moreover, when we used a CXCL12flox/flox; Prx1-Cre mice to selectively deplete chemotactic mechanism of the MSC, we found that PQ exposure in these mice failed to activate pro-fibrotic pathways including TGF-β, Wnt and EGFR signaling. Furthermore, when the chemotactic effect of MSCs via CXCL12 was blocked by a pharmacologic agent, AMD3100, it alleviated the development of the fibrotic process and improved survival rate in mice exposed to PQ. Conclusion: Collectively, our data suggest paraquat intoxication rapidly activated Nestin + MSCs and that blocking chemotactic effects of MSCs by perivascular CXCL12 inhibition may effectively protect pulmonary injury following paraquat exposure. Our results revealed a novel mechanism for post-PQ lung injury and indicated a novel therapeutic option to attenuate fibrosis induced by paraquat.

    Original languageEnglish (US)
    Pages (from-to)1-10
    Number of pages10
    JournalToxicology Letters
    Volume307
    DOIs
    StatePublished - Jun 1 2019

    Fingerprint

    Paraquat
    Pulmonary Fibrosis
    Mesenchymal Stromal Cells
    Cells
    Stem cells
    Nestin
    Lung Injury
    Fibrosis
    Inhibition (Psychology)
    Antidotes
    Poisoning
    Suicide
    Extracellular Matrix
    Smooth Muscle
    Actins
    China
    Collagen
    Muscle

    Keywords

    • AMD3100
    • CXCL12
    • Mesenchymal stromal cells
    • Paraquat
    • Pulmonary fibrosis

    ASJC Scopus subject areas

    • Toxicology

    Cite this

    Inhibition of mesenchymal stromal cells’ chemotactic effect to ameliorate paraquat-induced pulmonary fibrosis. / Zhang, Hongliang; Xiao, Bing; Jiang, Li; Yao, Wei; Shen, Huahao; Xiang, Xudong.

    In: Toxicology Letters, Vol. 307, 01.06.2019, p. 1-10.

    Research output: Contribution to journalArticle

    Zhang, Hongliang ; Xiao, Bing ; Jiang, Li ; Yao, Wei ; Shen, Huahao ; Xiang, Xudong. / Inhibition of mesenchymal stromal cells’ chemotactic effect to ameliorate paraquat-induced pulmonary fibrosis. In: Toxicology Letters. 2019 ; Vol. 307. pp. 1-10.
    @article{5ff3cfaf2ed24b008e4be9beab17a9a8,
    title = "Inhibition of mesenchymal stromal cells’ chemotactic effect to ameliorate paraquat-induced pulmonary fibrosis",
    abstract = "Background: Paraquat (PQ) poisoning is one of the leading causes of suicide attempts in China signature by acute onset of respiratory distress with massive matrix production resulting in progressive pulmonary fibrosis. There is no specific antidote and mortality remains high without effective treatment available. The cellular mechanisms underlying PQ-induced pulmonary fibrosis remain largely unknown. Objectives: To determine the origin of mesenchymal stem cells (MSCs) migrated to the lung after PQ exposure and their roles in PQ-induced pulmonary fibrosis, to further explore the possible mechanisms involved in these processes, and to help finding novel therapies. Methods: We used a combination of lineage tracking techniques to investigate the contributions of several cells of MSCs, marked by Nestin or CXCL12, and traced their co-expression of α-smooth muscle actin (α-SMA), a marker for fibrosis, or their co-location with matrix production, marked by collagen-1 production (Col1-GFP) following PQ exposure. Then, we used a CXCL12flox/flox; Prx1-Cre mice and a pharmacologic agent AMD3100 to selectively deplete chemotactic mechanism of the MSCs, and tested pro-fibrotic pathways, fibrotic processes and survival of mice after PQ exposure. Results: Our results showed that after paraquat exposure, the residential Nestin + MSCs were quickly expanded and contributed to extracellular matrix production. Moreover, when we used a CXCL12flox/flox; Prx1-Cre mice to selectively deplete chemotactic mechanism of the MSC, we found that PQ exposure in these mice failed to activate pro-fibrotic pathways including TGF-β, Wnt and EGFR signaling. Furthermore, when the chemotactic effect of MSCs via CXCL12 was blocked by a pharmacologic agent, AMD3100, it alleviated the development of the fibrotic process and improved survival rate in mice exposed to PQ. Conclusion: Collectively, our data suggest paraquat intoxication rapidly activated Nestin + MSCs and that blocking chemotactic effects of MSCs by perivascular CXCL12 inhibition may effectively protect pulmonary injury following paraquat exposure. Our results revealed a novel mechanism for post-PQ lung injury and indicated a novel therapeutic option to attenuate fibrosis induced by paraquat.",
    keywords = "AMD3100, CXCL12, Mesenchymal stromal cells, Paraquat, Pulmonary fibrosis",
    author = "Hongliang Zhang and Bing Xiao and Li Jiang and Wei Yao and Huahao Shen and Xudong Xiang",
    year = "2019",
    month = "6",
    day = "1",
    doi = "10.1016/j.toxlet.2019.01.005",
    language = "English (US)",
    volume = "307",
    pages = "1--10",
    journal = "Toxicology Letters",
    issn = "0378-4274",
    publisher = "Elsevier BV",

    }

    TY - JOUR

    T1 - Inhibition of mesenchymal stromal cells’ chemotactic effect to ameliorate paraquat-induced pulmonary fibrosis

    AU - Zhang, Hongliang

    AU - Xiao, Bing

    AU - Jiang, Li

    AU - Yao, Wei

    AU - Shen, Huahao

    AU - Xiang, Xudong

    PY - 2019/6/1

    Y1 - 2019/6/1

    N2 - Background: Paraquat (PQ) poisoning is one of the leading causes of suicide attempts in China signature by acute onset of respiratory distress with massive matrix production resulting in progressive pulmonary fibrosis. There is no specific antidote and mortality remains high without effective treatment available. The cellular mechanisms underlying PQ-induced pulmonary fibrosis remain largely unknown. Objectives: To determine the origin of mesenchymal stem cells (MSCs) migrated to the lung after PQ exposure and their roles in PQ-induced pulmonary fibrosis, to further explore the possible mechanisms involved in these processes, and to help finding novel therapies. Methods: We used a combination of lineage tracking techniques to investigate the contributions of several cells of MSCs, marked by Nestin or CXCL12, and traced their co-expression of α-smooth muscle actin (α-SMA), a marker for fibrosis, or their co-location with matrix production, marked by collagen-1 production (Col1-GFP) following PQ exposure. Then, we used a CXCL12flox/flox; Prx1-Cre mice and a pharmacologic agent AMD3100 to selectively deplete chemotactic mechanism of the MSCs, and tested pro-fibrotic pathways, fibrotic processes and survival of mice after PQ exposure. Results: Our results showed that after paraquat exposure, the residential Nestin + MSCs were quickly expanded and contributed to extracellular matrix production. Moreover, when we used a CXCL12flox/flox; Prx1-Cre mice to selectively deplete chemotactic mechanism of the MSC, we found that PQ exposure in these mice failed to activate pro-fibrotic pathways including TGF-β, Wnt and EGFR signaling. Furthermore, when the chemotactic effect of MSCs via CXCL12 was blocked by a pharmacologic agent, AMD3100, it alleviated the development of the fibrotic process and improved survival rate in mice exposed to PQ. Conclusion: Collectively, our data suggest paraquat intoxication rapidly activated Nestin + MSCs and that blocking chemotactic effects of MSCs by perivascular CXCL12 inhibition may effectively protect pulmonary injury following paraquat exposure. Our results revealed a novel mechanism for post-PQ lung injury and indicated a novel therapeutic option to attenuate fibrosis induced by paraquat.

    AB - Background: Paraquat (PQ) poisoning is one of the leading causes of suicide attempts in China signature by acute onset of respiratory distress with massive matrix production resulting in progressive pulmonary fibrosis. There is no specific antidote and mortality remains high without effective treatment available. The cellular mechanisms underlying PQ-induced pulmonary fibrosis remain largely unknown. Objectives: To determine the origin of mesenchymal stem cells (MSCs) migrated to the lung after PQ exposure and their roles in PQ-induced pulmonary fibrosis, to further explore the possible mechanisms involved in these processes, and to help finding novel therapies. Methods: We used a combination of lineage tracking techniques to investigate the contributions of several cells of MSCs, marked by Nestin or CXCL12, and traced their co-expression of α-smooth muscle actin (α-SMA), a marker for fibrosis, or their co-location with matrix production, marked by collagen-1 production (Col1-GFP) following PQ exposure. Then, we used a CXCL12flox/flox; Prx1-Cre mice and a pharmacologic agent AMD3100 to selectively deplete chemotactic mechanism of the MSCs, and tested pro-fibrotic pathways, fibrotic processes and survival of mice after PQ exposure. Results: Our results showed that after paraquat exposure, the residential Nestin + MSCs were quickly expanded and contributed to extracellular matrix production. Moreover, when we used a CXCL12flox/flox; Prx1-Cre mice to selectively deplete chemotactic mechanism of the MSC, we found that PQ exposure in these mice failed to activate pro-fibrotic pathways including TGF-β, Wnt and EGFR signaling. Furthermore, when the chemotactic effect of MSCs via CXCL12 was blocked by a pharmacologic agent, AMD3100, it alleviated the development of the fibrotic process and improved survival rate in mice exposed to PQ. Conclusion: Collectively, our data suggest paraquat intoxication rapidly activated Nestin + MSCs and that blocking chemotactic effects of MSCs by perivascular CXCL12 inhibition may effectively protect pulmonary injury following paraquat exposure. Our results revealed a novel mechanism for post-PQ lung injury and indicated a novel therapeutic option to attenuate fibrosis induced by paraquat.

    KW - AMD3100

    KW - CXCL12

    KW - Mesenchymal stromal cells

    KW - Paraquat

    KW - Pulmonary fibrosis

    UR - http://www.scopus.com/inward/record.url?scp=85062010419&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85062010419&partnerID=8YFLogxK

    U2 - 10.1016/j.toxlet.2019.01.005

    DO - 10.1016/j.toxlet.2019.01.005

    M3 - Article

    C2 - 30658152

    AN - SCOPUS:85062010419

    VL - 307

    SP - 1

    EP - 10

    JO - Toxicology Letters

    JF - Toxicology Letters

    SN - 0378-4274

    ER -