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 language | English (US) |
|---|---|
| Pages (from-to) | 1-10 |
| Number of pages | 10 |
| Journal | Toxicology Letters |
| Volume | 307 |
| DOIs | |
| State | Published - Jun 1 2019 |
Fingerprint
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 journal › Article
}
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 -