CENP-U function on TNBC.

31 Background: Centromere protein (CENP-U) gene, as an important constitutive kinetochorecomponent, plays significant roles in cell caryomitosis. Our previous research found that about 25% of transgenic mice with CENP-U amplified had suffered breast cancer in body surface. Also, in highly aggressive breast cancer cell lines, CENP-U presented the highest expression. Furthermore, the CENP-U protein expression obviously increased in human invasive breast carcinoma compared with the normal gland and intra-ductal tissue.Here we aimed to investigate the biological functions and potential molecular mechanism of CENP-U in breast cancer tumorigenesis. Methods: Gene knockdown was accomplished by transient transfection. In addition, cell proliferation was analyzed with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay while cell apoptosis was measured by flow cytometry using an annexin V-FITC apoptosis detection kit. Then, VEGF secretion in the supernatant was detected with an enzyme-linked immunosorbent assay (ELISA). Furthermore,Vascular endothelial markers of nude mouse were discovered by immunohistochemistry. And the signaling activation in the breast cancer cells was accessed by western blot using specific antibodies. Results: We observed higher CENP-U expression in breast cancer compared to adjacent normal breast tissue, especially in TNBC.The MTT and EdU assay showed that CENP-U promoted the proliferation of the triple negative breast cancer (TNBC) cells while CENP-U downregulated promoted cell apoptosis. Furthermore, the ELISA results revealed that CENP-U significantly promoted the production and secretion of VEGF in TNBC cells. In addition, CENP-U downregulated inhibits tumor growth and angiogenesis in vivo. Importantly, CENP-U targeted HIF-1α,VEGFA and COX-2, which were shown by the specific antibodies in the western blot. Conclusions: The results showed that CENP-U influence the proliferation, apoptosis and angiogenesis especially of TNBC cells. But the affected signaling pathways require further study.

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CENP-U function on TNBC.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e12546 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e12546-e12546

Author(s):

Jin Zhang

Keyword(s):

Breast Cancer ◽

Western Blot ◽

Cell Apoptosis ◽

Annexin V ◽

Breast Cancer Cell Lines ◽

Enzyme Linked Immunosorbent Assay ◽

Specific Antibodies ◽

Apoptosis Detection ◽

Signaling Activation

e12546 Background: Centromere protein (CENP-U) gene, as an important constitutive kinetochore component, plays significant roles in cell caryomitosis. Our previous research found that about 25 % of transgenic mice with CENP-U amplified had suffered breast cancer in body surface. Also, in highly aggressive breast cancer cell lines, CENP-U presented the highest expression. Furthermore, the CENP-U protein expression obviously increased in human invasive breast carcinoma compared with the normal gland and intra-ductal tissue. Methods: Gene knockdown was accomplished by transient transfection. In addition, cell proliferation was analyzed with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay while cell apoptosis was measured by flow cytometry using an annexin V-FITC apoptosis detection kit. Then, VEGF secretion in the supernatant was detected with an enzyme-linked immunosorbent assay (ELISA). Furthermore,Vascular endothelial markers of nude mouse were discovered by immunohistochemistry. And the signaling activation in the breast cancer cells was accessed by western blot using specific antibodies. Results: The MTT and EdU assay showed that CENP-U promoted the proliferation of the triple negative breast cancer (TNBC) cells while CENP-U downregulated promoted cell apoptosis. Furthermore, the ELISA results revealed that CENP-U significantly promoted the production and secretion of VEGF in TNBC cells. In addition, CENP-U downregulated inhibits tumor growth and angiogenesis in vivo. Importantly, CENP-U targeted HIF-1α,VEGFA, p-AKT and stat3, which were shown by the specific antibodies in the western blot. Conclusions: The results showed that CENP-U influence the proliferation, apoptosis and angiogenesis especially of TNBC cells. But the affected signaling pathways require further study.

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Chidamide Combined with Doxorubicin Induced p53-Driven Cell Cycle Arrest and Cell Apoptosis Reverse Multidrug Resistance of Breast Cancer

10.21203/rs.3.rs-67615/v1 ◽

2020 ◽

Author(s):

Lixia CAO ◽

Shaorong Zhao ◽

Qianxi Yang ◽

Zhendong Shi ◽

Jingjing Liu ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Apoptosis ◽

Breast Cancer Cell Lines ◽

Tunel Staining ◽

Drug Resistant ◽

Cycle Arrest ◽

Resistant Cells

Abstract Background The multidrug-resistant (MDR) phenotype is usually accompanied by an abnormal expression of histone deacetylase (HDAC). Given that HDAC is vital in chromatin remodeling and epigenetics, inhibiting the role of HDAC has become an important approach for tumor treatment. However, the effect of HDAC inhibitors on MDR breast cancer has not been elucidated. This study aimed to evaluate the resistance of two MDR breast cancer cell lines to the HDAC-selective inhibitor chidamide (CHI). Methods Cell viability, cell cycle and apoptosis were detected by CCK8, crystal violet staining, EDU staining, TUNEL assay, flow cytometry. The expression of HDAC1, H3K9, H3K18, p53, p21, caspase3/7/9 and the Bcl family was analyzed by western blotting and Quantitative real-time PCR. MDR breast cancer growth suppression by CHI and/or doxorubicin (DOX) in vivo was investigated in a tumor xenograft mouse model. Results The results showed that, CHI combined with DOX showed significant cytotoxicity to MDR breast cancer cells in vitro and in vivo compared with the CHI monotherapy. The cell cycle distribution results showed that CHI caused G0/G1 cell cycle arrest and inhibited cell growth regardless of the addition of DOX. At the same time, Annexin V staining and TUNEL staining results showed that CHI enhanced the number of cell apoptosis in drug-resistant cells. The western blot analysis found that p53 as a tumor suppressor was in a silent state in drug-resistant cells. However, p53 was activated in the CHI-treated and combined treatment groups, which, in turn, activated the p53 up-regulated apoptosis regulator recombinant protein (Puma) and pro-apoptotic protein Bax, downregulated the apoptotic proteins Bcl-xL and Bcl-2, and activated the caspase cascade to induce apoptosis. Conclusion The irreversible cell stress induced by CHI combined with DOX reduced the expression of HDAC1 and activated caspase-dependent apoptosis and p21-mediated growth arrest pathway, which might have been driven by the activation of p53. This provided a strong theoretical basis for exploring the treatment strategy of the combined use of CHI in patients with breast cancer who did not respond to chemotherapy or had cancer progression.

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Study on the Anticancer Effect of an Astragaloside- and Chlorogenic Acid-Containing Herbal Medicine (RLT-03) in Breast Cancer

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/1515081 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Yanchu Li ◽

Xianyong Li ◽

Chen Cuiping ◽

Rong Pu ◽

Yin Weihua

Keyword(s):

Breast Cancer ◽

Chlorogenic Acid ◽

Cell Apoptosis ◽

Tumor Volume ◽

Xenograft Model ◽

Breast Cancer Cell Lines ◽

Therapeutic Effects ◽

Dependent Manner ◽

Radix Astragali

Background. Although surgery, chemotherapy, radiotherapy, and endocrine therapy are widely used in clinical practice for breast cancer treatment, herbal medicines (HMs) are considered as an alternative to palliative treatments because of their coordinated intervention effects and relatively low side effects. Astragaloside (AS) and chlorogenic acid (CGA) are major active ingredients of Radix Astragali and Lonicera japonica, which have shown antitumorigenic properties in certain cancers, but the role of HMs containing both AS and CGA remains unclear in breast cancer. In this study, we explored an AS- and CGA-containing HM (RLT-03) extracted from Radix Astragali, Lonicerae Japonicae Flos, Trichosanthin, and Rhizoma imperatae. Methods. RLT-03 was extracted using water and n-butanol, and the AS and CGA ingredients in RLT-03 were identified by high-performance liquid chromatography (HPLC) and evaporative light-scattering detector (ELSD). 4T1, EMT6, BT-549, and MDA-MB-231 breast cancer cell lines were used, and an EMT6 xenograft model was established. Cell proliferation, migration, and apoptosis were measured in vitro, and tumor volume and weight were observed in vivo. The expression of VEGF, EGF, IL-10, TGF-β, and CD34 and cell apoptosis in tumors were examined. Results. RLT-03 inhibited cell viability and induced apoptosis in a dose- and time-dependent manner. In vivo, tumor volume and weight were reduced, and the expression of VEGF, EGF, IL-10, TGF-β, and CD34 was suppressed in the tumor microenvironment, while cell apoptosis was induced. Conclusion. RLT-03 exhibited therapeutic effects against breast cancer by regulating the expression of ligands of receptor tyrosine kinases (RTKs) and inflammatory factors. Thus, RLT-03 represents a potential supplementary HM that can be used in breast cancer therapy.

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2-hexyl-4-pentynoic acid (HPTA), a novel radiosensitizer to breast cancer cells through increasing the instability of DNA repair proteins

10.21203/rs.3.rs-80703/v1 ◽

2020 ◽

Author(s):

Zuchao Cai ◽

David Lim ◽

Guochao Liu ◽

Wenwen Ding ◽

Zhendong Wang ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Homologous Recombination ◽

Western Blot ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Breast Cancer Cell Lines ◽

Homologous Recombination Pathway ◽

Recombination Pathway

Abstract Background Breast cancer is one of the most common malignant tumors in the world which is the main cause of cancer death for women. Radiotherapy is the main treatment. Although some drugs have been found to enhance the effect of radiotherapy, there are also obvious deficiencies. Therefore, recent applied clinical research has been focusing on locating a suitable radiosensitizer to breast cancer radiotherapy. Methods MTT, clonogenic survival assays, comet assays, immunofluorescence and western blot analyses were used to detect the effect of VPA / HPTA on DNA damage induced by radiotherapy for breast cancer through a variety of cell models( MCF7, EUFA423, HCC1937, DMBA-induced rat breast cancer-derived primary culture cell and DMBA-induced transformed human normal breast cell line). At the same time, flow cytometry, immunofluorescence and western blot analyses were used to investigate the effect of VPA / HPTA on DNA damage repair induced by radiation. In vivo experiment, the effect of HPTA as radiosensitizer was investigated by DMBA-induced breast cancer in rats. Finally, the possible mechanism of HPTA acting on target protein was proved by cycloheximide chase experiment. Results In this study, a derivative of valproic acid (VPA), 2-hexyl-4-pentynoic acid (HPTA), was demonstrated for the first time that low concentration of HPTA (15 µM) has radiosensitizing properties to breast cancer cells by multiple working models of breast cancer cell lines (in vivo), equivalent to a high concentration of VPA (500 µM). Mechanistic investigations revealed that HPTA induced radiosensitivity through inhibiting the BRCA1-Rad51-mediated homologous recombination pathway. These results were further manifested in breast cancer animal model (in vitro). Most importantly, our study found that HPTA influenced the stability of BRCA1 and Rad51 proteins via shorting their half-life. Conclusions Our findings support the proposition HPTA as an alternate, safe and effective radiosensitizer to tumor cells. Targeting BRCA1-Rad51-mediated homologous recombination pathway through HPTA may be a rational strategy to improve the radiotherapeutic efficacy of breast cancer.

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Chidamide combined with doxorubicin induced p53-driven cell cycle arrest and cell apoptosis reverse multidrug resistance of breast cancer

10.21203/rs.3.rs-67615/v2 ◽

2020 ◽

Author(s):

Lixia CAO ◽

Shaorong Zhao ◽

Qianxi Yang ◽

Zhendong Shi ◽

Jingjing Liu ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Apoptosis ◽

Breast Cancer Cell Lines ◽

Tunel Staining ◽

Drug Resistant ◽

Cycle Arrest ◽

Resistant Cells

Abstract Background: The multidrug-resistant (MDR) phenotype is usually accompanied by an abnormal expression of histone deacetylase (HDAC). Given that HDAC is vital in chromatin remodeling and epigenetics, inhibiting the role of HDAC has become an important approach for tumor treatment. However, the effect of HDAC inhibitors on MDR breast cancer has not been elucidated. This study aimed to evaluate the resistance of two MDR breast cancer cell lines to the HDAC-selective inhibitor chidamide (CHI).Methods: Cell viability, cell cycle and apoptosis were detected by CCK8, crystal violet staining, EDU staining, TUNEL assay, flow cytometry. The expression of HDAC1, H3K9, H3K18, p53, p21, caspase3/7/9 and the Bcl family was analyzed by western blotting and Quantitative real-time PCR. MDR breast cancer growth suppression by CHI and/or doxorubicin (DOX) in vivo was investigated in a tumor xenograft mouse model.Results: The results showed that, CHI combined with DOX showed significant cytotoxicity to MDR breast cancer cells in vitro and in vivo compared with the CHI monotherapy. The cell cycle distribution results showed that CHI caused G0/G1 cell cycle arrest and inhibited cell growth regardless of the addition of DOX. At the same time, Annexin V staining and TUNEL staining results showed that CHI enhanced the number of cell apoptosis in drug-resistant cells. The western blot analysis found that p53 as a tumor suppressor was in a silent state in drug-resistant cells. However, p53 was activated in the CHI-treated and combined treatment groups, which, in turn, activated the p53 up-regulated apoptosis regulator recombinant protein (Puma) and pro-apoptotic protein Bax, downregulated the apoptotic proteins Bcl-xL and Bcl-2, and activated the caspase cascade to induce apoptosis. Conclusion: The irreversible cell stress induced by CHI combined with DOX reduced the expression of HDAC1 and activated caspase-dependent apoptosis and p21-mediated growth arrest pathway, which might have been driven by the activation of p53. This provided a strong theoretical basis for exploring the treatment strategy of the combined use of CHI in patients with breast cancer who did not respond to chemotherapy or had cancer progression.

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LPTO-06. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.029 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i7-i7

Author(s):

Jiaojiao Deng ◽

Sophia Chernikova ◽

Wolf-Nicolas Fischer ◽

Kerry Koller ◽

Bernd Jandeleit ◽

...

Keyword(s):

Breast Cancer ◽

Brain Tumors ◽

Cell Lines ◽

Chemotherapeutic Agent ◽

Leptomeningeal Metastasis ◽

Breast Cancer Cell Lines ◽

Normal Brain ◽

Breast Cancers

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

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CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22115782 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5782

Author(s):

Ashwini Makhale ◽

Devathri Nanayakkara ◽

Prahlad Raninga ◽

Kum Kum Khanna ◽

Murugan Kalimutho

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Triple Negative Breast Cancer ◽

Combination Treatment ◽

Triple Negative ◽

Annexin V ◽

Replication Stress ◽

Breast Cancer Cell Lines ◽

Combination Strategy

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of individual and combination therapy of CX-5461 and APR-246 in vitro, using a panel of breast cancer cell lines. Using publicly available breast cancer datasets, we found that components of RNA Pol I are predominately upregulated in basal-like breast cancer, compared to other subtypes, and this upregulation is associated with poor overall and relapse-free survival. Notably, we found that the treatment of breast cancer cells lines with CX-5461 significantly hampered cell proliferation and synergistically enhanced the efficacy of APR-246. The combination treatment significantly induced apoptosis that is associated with cleaved PARP and Caspase 3 along with Annexin V positivity. Likewise, we also found that combination treatment significantly induced DNA damage and replication stress in these cells. Our data provide a novel combination strategy by utilizing APR-246 in combination CX-5461 in killing TNBC cells that can be further developed into more effective therapy in TNBC therapeutic armamentarium.

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MRCKα Is Dispensable for Breast Cancer Development in the MMTV-PyMT Model

Cells ◽

10.3390/cells10040942 ◽

2021 ◽

Vol 10 (4) ◽

pp. 942

Author(s):

Mei Qi Kwa ◽

Rafael Brandao ◽

Trong H. Phung ◽

Jianfeng Ge ◽

Giuseppe Scieri ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression Signature ◽

Genomic Analysis ◽

Cancer Development ◽

Breast Cancer Cell Lines ◽

Normal Mammary Gland ◽

Breast Cancers ◽

Human Breast ◽

Breast Cancer Development

MRCKα is a ubiquitously expressed serine/threonine kinase involved in cell contraction and F-actin turnover, which is highly amplified in human breast cancer and part of a gene expression signature for bad prognosis. Nothing is known about the in vivo function of MRCKα. To explore MRCKα function in development and in breast cancer, we generated mice lacking a functional MRCKα gene. Mice were born close to the Mendelian ratio and showed no obvious phenotype including a normal mammary gland formation. Assessing breast cancer development using the transgenic MMTV-PyMT mouse model, loss of MRCKα did not affect tumor onset, tumor growth and metastasis formation. Deleting MRCKα and its related family member MRCKβ in two triple-negative breast cancer cell lines resulted in reduced invasion of MDA-MB-231 cells, but did not affect migration of 4T1 cells. Further genomic analysis of human breast cancers revealed that MRCKα is frequently co-amplified with the oncogenes ARID4B and AKT3 which might contribute to the prognostic value of MRCKα expression. Collectively, these data suggest that MRCKα might be a prognostic marker for breast cancer, but probably of limited functional importance.

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NEAT1 aggravates sepsis-induced acute kidney injury by sponging miR-22-3p

Open Medicine ◽

10.1515/med-2020-0401 ◽

2020 ◽

Vol 15 (1) ◽

pp. 333-342

Author(s):

Yawei Feng ◽

Jun Liu ◽

Ranliang Wu ◽

Peng Yang ◽

Zhiqiang Ye ◽

...

Keyword(s):

Acute Kidney Injury ◽

Western Blot ◽

Cell Apoptosis ◽

Noncoding Rna ◽

Cell Injury ◽

Kidney Injury ◽

Inflammatory Factors ◽

Luciferase Reporter ◽

Enzyme Linked Immunosorbent Assay ◽

Western Blot Assay

AbstractBackground and aimAcute kidney injury (AKI) is a common complication of sepsis. Long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) plays a vital role in various diseases, including AKI. This study aimed to investigate the function and mechanism of NEAT1 in sepsis-induced AKI.Materials and methodsA septic AKI model was established by treating HK-2 cells with lipopolysaccharide (LPS). The levels of NEAT1 and miR-22-3p were measured by quantitative real-time PCR. Cell apoptosis was assessed by flow cytometry. The levels of apoptosis-related protein and autophagy-related factors were examined by the western blot assay. An enzyme-linked immunosorbent assay was used to calculate the contents of inflammatory factors. The interaction between NEAT1 and miR-22-3p was validated by dual-luciferase reporter assay, RNA immunoprecipitation assay, and RNA pull-down assay. The levels of nuclear factor (NF)-κB pathway-related proteins were evaluated by the western blot assay.ResultsNEAT1 was upregulated, while miR-22-3p was downregulated in patients with sepsis and in LPS-stimulated HK-2 cells. LPS treatment triggered cell apoptosis, autophagy, and inflammatory response in HK-2 cells. NEAT1 knockdown attenuated LPS-induced cell injury. NEAT1 modulated LPS-triggered cell injury by targeting miR-22-3p. Furthermore, NEAT1 regulated the NF-κB pathway by modulating miR-22-3p.ConclusionDepletion of NEAT1 alleviated sepsis-induced AKI via regulating the miR-22-3p/NF-κB pathway.

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Annexin V decreases PS-mediated macrophage efferocytosis and deteriorates elastase-induced pulmonary emphysema in mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00066.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. L852-L860 ◽

Cited By ~ 13

Author(s):

S. Yoshida ◽

N. Minematsu ◽

S. Chubachi ◽

H. Nakamura ◽

M. Miyazaki ◽

...

Keyword(s):

Mrna Expression ◽

Cell Apoptosis ◽

Pulmonary Emphysema ◽

Keratinocyte Growth Factor ◽

Annexin V ◽

Phenotypic Change ◽

Chronic Obstructive ◽

Mrna Levels

Efferocytosis is believed to be a key regulator for lung inflammation in chronic obstructive pulmonary disease. In this study we pharmacologically inhibited efferocytosis with annexin V and attempted to determine its impact on the progression of pulmonary emphysema in mouse. We first demonstrated in vitro and in vivo efferocytosis experiments using annexin V, an inhibitor for phosphatidylserine-mediated efferocytosis. We then inhibited efferocytosis in porcine pancreatic elastase (PPE)-treated mice. PPE-treated mice were instilled annexin V intranasally starting from day 8 until day 20. Mean linear intercept (Lm) was measured, and cell apoptosis was assessed in lung specimen obtained on day 21. Cell profile, apoptosis, and mRNA expression of matrix metalloproteinases (MMPs) and growth factors were evaluated in bronchoalveolar lavage (BAL) cells on day 15. Annexin V attenuated macrophage efferocytosis both in vitro and in vivo. PPE-treated mice had a significant higher Lm, and annexin V further increased that by 32%. More number of macrophages was found in BAL fluid in this group. Interestingly, cell apoptosis was not increased by annexin V treatment both in lung specimens and BAL fluid, but macrophages from mice treated with both PPE and annexin V expressed higher MMP-2 mRNA levels and had a trend for higher MMP-12 mRNA expression. mRNA expression of keratinocyte growth factor tended to be downregulated. We showed that inhibited efferocytosis with annexin V worsened elastase-induced pulmonary emphysema in mice, which was, at least partly, attributed to a lack of phenotypic change in macrophages toward anti-inflammatory one.

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