Selective M2 Macrophage Depletion Leads to Prolonged Inflammation in Surgical Wounds

2017 ◽  
Vol 58 (3-4) ◽  
pp. 109-120 ◽  
Author(s):  
Kerstin Klinkert ◽  
Derek Whelan ◽  
Anthony J.P. Clover ◽  
Anne-Laure Leblond ◽  
Arun H.S. Kumar ◽  
...  
Keyword(s):  
Wound Healing ◽  
Cell Tracking ◽  
Chronic Wounds ◽  
Fluorescent Protein ◽  
Kinase Inhibitor ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Inflammatory Phase ◽  
Surgical Wounds

Background: A prolonged inflammatory phase is seen in aberrant wound healing and in chronic wounds. Macrophages are central to wound healing. Distinct macrophage subtypes have differing roles both in initial inflammation and in later tissue repair. Broadly, these cells can be divided into M1 and M2 macrophages. M2 macrophage proliferation and differentiation is regulated by colony-stimulating factor 1 (CSF-1) signalling and can be blocked by GW2580, a competitive cFMS kinase inhibitor, thereby allowing for analysis of the effect of M2 blockade on progression of surgical wounds. Materials and Methods: Macrophage Fas-induced apoptosis (MaFIA) transgenic mice with a macrophage-specific promoter used to express green fluorescent protein (GFP) were used to allow for cell tracking. The animals were treated by oral gavage with GW2580. Surgical wounds were created and harvested after 2 weeks for analysis. Results: GW2580-treated mice had significantly more GFP+ cells in the surgical scar than vehicle-treated animals (GW2580, 68.0 ± 3.1%; vehicle, 42.8 ± 1.7%; p < 0.001), and GW2580 treatment depleted CD206+ M2 macrophages in the scar (GW2580, 1.4%; vehicle, 19.3%; p < 0.001). Treated animals showed significantly higher numbers of neutrophils (vehicle, 18.0%; GW2580, 51.3%; p < 0.01) and M1 macrophages (vehicle, 3.8%; GW2580, 12.8%; p < 0.01) in the scar compared to vehicle-treated animals. The total collagen content in the area of the scar was decreased in animals treated with GW2580 as compared to those treated with vehicle alone (GW2580, 67.1%; vehicle, 79.9%; p < 0.005). Conclusions: Depletion of M2 macrophages in surgical wounds via CSF-1 signalling blockade leads to persistent inflammation, with an increase in neutrophils and M1 macrophages and attenuated collagen deposition.

scholarly journals Hypoxia impairs mesenchymal stromal cell-induced macrophage M1 to M2 transition

TECHNOLOGY ◽  
2017 ◽  
Vol 05 (02) ◽  
pp. 81-86 ◽  
Author(s):  
Renea A. Faulknor ◽  
Melissa A. Olekson ◽  
Emmanuel C. Ekwueme ◽  
Paulina Krzyszczyk ◽  
Joseph W. Freeman ◽  
...  
Keyword(s):  
Wound Healing ◽  
Chronic Wounds ◽  
Interleukin 10 ◽  
M2 Macrophage ◽  
Therapeutic Effects ◽  
M1 Macrophages ◽  
Normal Wound Healing ◽  
Hypoxic Environment ◽  
Anti Inflammatory ◽  
M2 Phenotype

The transition of macrophages from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype is crucial for the progression of normal wound healing. Persistent M1 macrophages within the injury site may lead to an uncontrolled macrophage-mediated inflammatory response and ultimately a failure of the wound healing cascade, leading to chronic wounds. Mesenchymal stromal cells (MSCs) have been widely reported to promote M1 to M2 macrophage transition; however, it is unclear whether MSCs can drive this transition in the hypoxic environment typically observed in chronic wounds. Here we report on the effect of hypoxia (1% O[Formula: see text] on MSCs’ ability to transition macrophages from the M1 to the M2 phenotype. While hypoxia had no effect on MSC secretion, it inhibited MSC-induced M1 to M2 macrophage transition, and suppressed macrophage expression and production of the anti-inflammatory mediator interleukin-10 (IL-10). These results suggest that hypoxic environments may impede the therapeutic effects of MSCs.

scholarly journals Blocking AGE-RAGE Signaling Improved Functional Disorders of Macrophages in Diabetic Wound

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Qi Wang ◽  
Guanya Zhu ◽  
Xiaozan Cao ◽  
Jiaoyun Dong ◽  
Fei Song ◽  
...  
Keyword(s):  
Wound Healing ◽  
Early Stage ◽  
Control Group ◽  
M2 Macrophages ◽  
Functional Disorders ◽  
Proinflammatory Response ◽  
M1 Macrophages ◽  
Impaired Wound Healing ◽  
Inflammatory Phase ◽  
Diabetic Wounds

Advanced glycosylation end products (AGEs) accumulate in diabetic wounds. Interactions between AGEs and their receptor (RAGE) leads to dermatologic problems in diabetes. Macrophage, which plays important roles in wound healing, highly expresses RAGE. Therefore, we investigated whether RAGE-expressing macrophages might be responsible for impaired wound healing on diabetes. We used anti-RAGE antibody applied topically on diabetic wounds. After confirming that wound healing was improved in anti-RAGE antibody group compared with normal mice, our results showed that macrophages appeared insufficient in the early stage and fading away slowly in the later proliferative phase compared with the control group, which was ameliorated in anti-RAGE antibody-applied wounds. Blocking AGE-RAGE signaling also increased neutrophils phagocytized by macrophages and promoted the phenotypic switch of macrophages from proinflammatory to prohealing activities. In vitro, phagocytosis of THP-1 (M0) and lipopolysaccharide- (LPS-) induced (M1) macrophages was impaired by treatment with AGEs, while IL-4- and IL-13-induced (M2) macrophages was not. Finally, AGEs increased the proinflammatory response of M1 macrophages, while inhibiting the polarization and anti-inflammatory functions of M2 macrophages. In conclusion, inhibition of AGE-RAGE signaling improved functional disorders of macrophages in the early inflammatory phase, which promoted the healing of wounds in diabetic mice.

PHENOTYPIC HETEROGENEITY OF CARDIAC MACROPHAGES DURING WOUND HEALING FOLLOWING MYOCARDIAL INFARCTION: PERSPECTIVES IN CLINICAL RESEARCH

2018 ◽  
Vol 33 (2) ◽  
pp. 70-76 ◽  
Author(s):  
A. E. Gombozhapova ◽  
Yu. V. Rogovskaya ◽  
M. S. Rebenkova ◽  
J. G. Kzhyshkowska ◽  
V. V. Ryabov
Keyword(s):  
Myocardial Infarction ◽  
Wound Healing ◽  
Cardiac Remodeling ◽  
Phenotypic Heterogeneity ◽  
Macrophage Infiltration ◽  
Myocardial Regeneration ◽  
Control Group ◽  
M2 Macrophage ◽  
Inflammatory Phase ◽  
Regenerative Phase

Purpose. Myocardial regeneration is one of the most ambitious goals in prevention of adverse cardiac remodeling. Macrophages play a key role in transition from inflammatory to regenerative phase during wound healing following myocardial infarction (MI). We have accumulated data on macrophage properties ex vivo and in cell culture. However, there is no clear information about phenotypic heterogeneity of cardiac macrophages in patients with MI. The purpose of the project was to assess cardiac macrophage infiltration during wound healing following myocardial infarction in clinical settings taking into consideration experimental knowledge.Material and Methods. The study included 41 patients with fatal MI type 1. In addition to routine analysis, macrophages infiltration was assessed by immunohistochemistry. We used CD68 as a marker for the cells of the macrophage lineage, while CD163, CD206, and stabilin-1 were considered as M2 macrophage biomarkers. Nine patients who died from noncardiovascular causes comprised the control group.Results. The intensity of cardiac macrophage infiltration was higher during the regenerative phase than during the inflammatory phase. Results of immunohistochemical analysis demonstrated the presence of phenotypic heterogeneity of cardiac macrophages in patients with MI. We noticed that numbers of CD68+, CD163+, CD206+, and stabilin-1+ macrophages depended on MI phase.Conclusion. Our study supports prospects for implementation of macrophage phenotyping in clinic practice. Improved understanding of phenotypic heterogeneity might become the basis of a method to predict adverse cardiac remodeling and the first step in developing myocardial regeneration target therapy.

scholarly journals Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Keizo Kohno ◽  
Satomi Koya-Miyata ◽  
Akira Harashima ◽  
Takahiko Tsukuda ◽  
Masataka Katakami ◽  
...  
Keyword(s):  
Wound Healing ◽  
Chronic Wounds ◽  
Macrophage Polarization ◽  
Phenotypic Switching ◽  
Apoptotic Cells ◽  
Phenotypic Switch ◽  
Inflammatory Phase ◽  
M1 Macrophage ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Background NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase. Results NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86. Interestingly, NK-4 augmented TNF-α production by THP-1 macrophages in combination with LPS, Pam3CSK4, or poly(I:C). Furthermore, NK-4 treatment enhanced THP-1 macrophage phagocytosis of latex beads. These results indicate that NK-4 drives macrophage polarization toward an inflammatory M1-like phenotype with increased phagocytic activity. Efferocytosis is a crucial event for resolution of the inflammatory phase in wound healing. NK-4-treated THP-1 macrophages co-cultured with apoptotic Jurkat E6.1 (Apo-J) cells switched from an M1-like phenotype to an M2-like phenotype, as seen in the inverted ratio of TNF-α to IL-10 produced in response to LPS. We identified two separate mechanisms that are involved in this phenotypic switch. First, recognition of phosphatidylserine molecules on Apo-J cells by THP-1 macrophages downregulates TNF-α production. Second, phagocytosis of Apo-J cells by THP-1 macrophages and activation of PI3K/Akt signaling pathway upregulates IL-10 production. Conclusion It is postulated that the phenotypic switch from a proinflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site. Our results demonstrate that NK-4 improves phagocytosis of apoptotic cells, suggesting its potential as a therapeutic strategy to resolve sustained inflammation in chronic wounds.

Abstract 199: Type 2 Diabetes Impairs Wound Healing By DNMT1-dependent Reduction of Hematopoietic Stem Cell Differentiation towards Monocytes/Macrophages and Skewing of the M1/M2 Polarization

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Jinglian Yan ◽  
Guodong Tie ◽  
Lyne Khair ◽  
Elena Filippova ◽  
Louis Messina
Keyword(s):  
Type 2 Diabetes ◽  
Wound Healing ◽  
Epigenetic Modification ◽  
Stem Cell Differentiation ◽  
M1 Macrophages ◽  
Hematopoietic Stem ◽  
Impaired Wound Healing ◽  
Inflammatory Phase ◽  
M2 Polarization

Rationale: People with Type 2 Diabetes Mellitus (T2DM) have a 25x higher risk of limb loss than non-diabetics due in large part to impaired wound healing. The mechanisms that cause impaired wound healing remain incompletely characterized. Objective: We hypothesize that T2DM impairs wound healing by epigenetic modifications in hematopoietic stem cells (HSC) that reduce their differentiation towards monocytes/macrophages and disrupts the balance in M1/M2 polarization during the three phases of wound healing. Methods and Results: Wounds were created on the back of mice. Wound healing was significantly slower in diabetic db/db than in WT mice. During the early inflammatory phase, db/db wounds exhibited a significant decrease in total macrophages and M1 macrophages. Then, total macrophages and M2 macrophages were decreased, while M1 macrophages increased in tissue formation phase. In the late tissue remodeling phase, total macrophages and M1 macrophages were persistently increased. The impaired wound healing phenotype of db/db mice was recapitulated in WT recipients which were resconstituted with db/db HSCs, demonstrating that the impaired differentiation of HSCs towards macrophages as well as their M1/M2 polarization was due to a cell autonomous mechanism. Epigenetic studies indicated that DNMT1-dependent hypermethylation of Notch1, Pu.1 and KLF4 in T2D HSCs was responsible for the impaired differentiation towards monocytes/macrophages as well as the skewed M1/M2 polarization. Knockdown of DNMT1 in HSCs from db/db mice transplanted into lethally irradiated WT mice led to improved wound healing by an increase in macrophage infiltration as well as a normalization of the M1/M2 polarization. Conclusion: This study indicates that the dynamic changes of macrophage concentration and M1/M2 polarization in wound healing are regulated at the level of HSCs. Moreover, T2DM impairs wound healing by inducing DNMT1-dependent reduction of HSCs’ differentiation towards macrophages and their M1/M2 polarization. This novel finding indicates that inflammation is regulated at the level of HSCs, which creates new opportunities to develop epigenetic modification related therapies for T2DM and potentially other conditions that result from dysinflammation.

Abstract 660: Macrophage Specific Deficiency of the Transient Receptor Potential Canonical 3 Channel Reduces Apoptosis and Necrosis in Advanced Atherosclerotic Plaques

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Sumeet A Solanki ◽  
Guillermo Vazquez
Keyword(s):  
Bone Marrow ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Atherosclerotic Plaques ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Transient Receptor Potential Canonical ◽  
Transient Receptor ◽  
Apoptosis And Necrosis

Background: Macrophage apoptosis plays a critical role in progression of atherosclerosis. Previous studies suggest that M1 and M2 macrophage phenotypes dominate atherosclerosis. Recently, we showed that advanced lesions in the aortic root of Apoe -/- mice transplanted with bone marrow deficient in the calcium-permeable channel Transient Receptor Potential Canonical 3 (TRPC3) are characterized by reduced areas of necrosis and less apoptotic macrophages. However, the donor mice used in these studies had global deficiency of TRPC3, raising the question whether the observed phenotype was also contributed by TRPC3-deficient non-myeloid cells which could undermine the true impact of macrophage deletion of TRPC3. To address this important question, we generated mice with macrophage-specific loss of TRPC3 function (MacTrpc3 -/- ). Methods & results: 13 six week-old female Ldlr -/- mice were irradiated and transplanted with Ldlr -/- (control) or MacTrpc3 -/- Ldlr -/- (experimental) bone marrow and kept on high fat diet for 14 weeks. At the end of the diet period, aortic roots were sectioned and processed for atherosclerotic lesion analysis. Total lesion size (H&E), neutral lipid (Oil Red O) and macrophage content (CD68 staining) were not different between groups. However, we found a 1.7 fold decrease (P=0.01) in percent necrotic area in advanced lesions of MacTrpc3 -/- Ldlr -/- mice (23.12 ± 2.07%, n=10) compared to controls (39.63 ± 5.93%, n=10). Using in situ TUNEL we found that MacTrpc3 -/- Ldlr -/- lesions have less apoptotic cells compared to controls, and these overlapped with CD68 + areas. Using iNOS and mannose receptor as markers for M1 and M2 macrophages, respectively, we found that both subsets overlapped with CD68 + and TUNEL + positive areas, with no differences between groups (n=5). Previously, we showed that M1, but not M2 macrophages derived from MacTrpc3 -/- mice, had reduced apoptosis. This suggests that reduced plaque necrosis of MacTrpc3 -/- Ldlr -/- mice may be due to reduced apoptosis of M1 macrophages. In sum, these in vivo studies indicate that macrophage-specific deficiency of TRPC3 has a genuine beneficial effect on advanced atherosclerotic plaques, reducing apoptosis and necrosis, probably due to a selective effect of TRPC3 on M1 macrophages.

Bacteriophage Therapy of Chronic Nonhealing Wound: Clinical Study

2019 ◽  
Vol 18 (2) ◽  
pp. 171-175 ◽  
Author(s):  
Pooja Gupta ◽  
Hari Shankar Singh ◽  
Vijay K. Shukla ◽  
Gopal Nath ◽  
Satyanam Kumar Bhartiya
Keyword(s):  
Wound Healing ◽  
Biofilm Formation ◽  
Bacterial Infections ◽  
Chronic Wounds ◽  
Bacterial Count ◽  
Complete Healing ◽  
Resistant Bacteria ◽  
Bacteriophage Therapy ◽  
Inflammatory Phase ◽  
Drug Resistant Bacteria

Background: A chronic wound usually results due to halt in the inflammatory phase of wound healing. Bacterial infections and biofilm formation are considered to be the basic cause of it. Chronic wounds significantly impair the quality of life. Antibiotics are now failing due to biofilm formation emergence of drug-resistant bacteria. Objective: This study aims to see the effect of bacteriophage therapy in chronic nonhealing wound infected with the following bacteria: Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Subject: Patients with chronic nonhealing wound not responding to conventional local debridement and antibiotic therapy were included in the study. The age of patients ranged between 12 and 60 years. Method: A total of 20 patients selected and tissue biopsies and wound swabs were taken for isolation of the bacteria. After confirmation of organism, a cocktail of customized bacteriophages was topically applied over the wound on alternate days till the wound surface became microbiologically sterile. Mean bacterial count and clinical assessment were done and compared at the time of presentation and after 3 and 5 doses of application. Results: A significant improvement was observed in the wound healing, and there were no signs of infection clinically and microbiologically after 3 to 5 doses of topical bacteriophage therapy. Seven patients achieved complete healing on day21 during follow up while in others healthy margins and healthy granulation tissue were observed. Conclusion: Topical bacteriophage application may be quite effective therapy for the treatment of chronic nonhealing wounds.

scholarly journals Phenotype and function of macrophage polarization in monocrotaline-induced pulmonary arterial hypertension rat model

2021 ◽  
Author(s):  
Yong Fan ◽  
Yanjie Hao ◽  
Dai Gao ◽  
Lan Gao ◽  
Guangtao Li ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Lung Tissue ◽  
Rat Model ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by vascular remodeling and chronic inflammation. Macrophages are the key orchestrators of inflammatory and repair responses, and have been demonstrated to be vital in the pathogenesis of PAH. However, specific phenotype of macrophage polarization (M1 & M2 macrophage) in the development of PAH and the underlying mechanisms how they work are still largely unclear. A rat model of monocrotaline (MCT) induced PAH was used. Hemodynamic analysis and histopathological experiments were conducted at day 3, 7, 14, 21 and 28, respectively. In PAH rat lung tissue, confocal microscopic images showed that CD68+NOS2+ M1-like macrophages were remarkably infiltrated on early stage, but dramatically decreased in mid-late stage. Meanwhile, CD68+CD206+ M2-like macrophages in lung tissue accumulated gradually since day 7 to day 28, and the relative ratio of M2/M1 macrophage increased over time. Results detected by western blot and immunohistochemistry were consistent. Further vitro functional studies revealed the possible mechanism involved in this pathophysiological process. By using Transwell co-culture system, it was found that M1 macrophages induced endothelial cell apoptosis, while M2 macrophages significantly promoted proliferation of both endothelial cell and smooth muscle cell. These data preliminarily demonstrated a temporal dynamic change of macrophage M1/M2 polarization status in the development of experimental PAH. M1 macrophages participated in the initial stage of inflammation by accelerating apoptosis of endothelial cell, while M2 macrophages predominated in the reparative stage of inflammation and the followed stage of aberrant tissue remodeling.

scholarly journals Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

2020 ◽  
Author(s):  
Keizo Kohno ◽  
Satomi Koya-Miyata ◽  
Akira Harashima ◽  
Takahiko Tsukuda ◽  
Masataka Katakami ◽  
...  
Keyword(s):  
Wound Healing ◽  
Chronic Wounds ◽  
Macrophage Polarization ◽  
Poly I:C ◽  
Phenotypic Switching ◽  
Phenotypic Switch ◽  
Inflammatory Phase ◽  
Macrophage Phagocytosis ◽  
M1 Macrophage ◽  
Anti Inflammatory

Abstract Background: NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase. Results: NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86. Interestingly, NK-4 augmented TNF-a production by THP-1 macrophages in combination with LPS, Pam3CSK4, or poly(I:C). Furthermore, NK-4 treatment enhanced THP-1 macrophage phagocytosis. These results indicate that NK-4 drives macrophage polarization toward an inflammatory M1-like phenotype with increased phagocytic activity. Efferocytosis is a crucial event for resolution of the inflammatory phase in wound healing. NK-4-treated THP-1 macrophages co-cultured with apoptotic Jurkat E6.1 (Apo-J) cells switched from an M1-like phenotype to an M2-like phenotype, as seen in the inverted ratio of TNF-a to IL-10 produced in response to LPS. We identified two separate mechanisms that are involved in this phenotypic switch. First, recognition of phosphatidylserine molecules on Apo-J cells by THP-1 macrophages downregulates TNF-a production. Second, phagocytosis of Apo-J cells by THP-1 macrophages and activation of PI3K/Akt signaling pathway upregulates IL-10 production. Conclusion: It is postulated that the phenotypic switch from a proinflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site. Our results demonstrate that NK-4 improves efferocytosis, suggesting its potential as a therapeutic strategy to resolve sustained inflammation in chronic wounds.

scholarly journals Insights into Host–Pathogen Interactions in Biofilm-Infected Wounds Reveal Possibilities for New Treatment Strategies

Antibiotics ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 396
Author(s):  
Hannah Trøstrup ◽  
Anne Sofie Boe Laulund ◽  
Claus Moser
Keyword(s):  
Wound Healing ◽  
Host Response ◽  
Chronic Wounds ◽  
Therapeutic Potential ◽  
Recent Observation ◽  
Treatment Strategies ◽  
Normal Wound Healing ◽  
Inflammatory Phase ◽  
The Impact

Normal wound healing occurs in three phases—the inflammatory, the proliferative, and the remodeling phase. Chronic wounds are, for unknown reasons, arrested in the inflammatory phase. Bacterial biofilms may cause chronicity by arresting healing in the inflammatory state by mechanisms not fully understood. Pseudomonas aeruginosa, a common wound pathogen with remarkable abilities in avoiding host defense and developing microbial resistance by biofilm formation, is detrimental to wound healing in clinical studies. The host response towards P. aeruginosa biofilm-infection in chronic wounds and impact on wound healing is discussed and compared to our own results in a chronic murine wound model. The impact of P. aeruginosa biofilms can be described by determining alterations in the inflammatory response, growth factor profile, and count of leukocytes in blood. P. aeruginosa biofilms are capable of reducing the host response to the infection, despite a continuously sustained inflammatory reaction and resulting local tissue damage. A recent observation of in vivo synergism between immunomodulatory and antimicrobial S100A8/A9 and ciprofloxacin suggests its possible future therapeutic potential.

Sign in / Sign up

Export Citation Format

Share Document