Immunomodulatory Effects Of Macrolides Research Articles

The clarithromycin-binding proteins NIPSNAP1 and 2 regulate cytokine production through mitochondrial quality control

The mechanism underlying the anti-inflammatory effect of macrolide antibiotics, such as clarithromycin (CAM), remains to be clarified. The CAM-binding proteins 4-nitrophenylphosphatase domain and non-neuronal synaptosomal associated protein 25 (SNAP25)-like protein homolog (NIPSNAP) 1 and 2 are involved in the immune response and mitochondrial homeostasis. However, the axis between CAM-NIPSNAP-mitochondria and Toll-like receptor (TLR) and their molecular mechanisms remain unknown. In this study, we sought to elucidate the relationship between mitochondrial homeostasis mediated by NIPSNAP1 and 2 and the immunomodulatory effect of CAM. NIPSNAP1 or 2 knockdown (KD) by RNA interference impaired TLR4-mediated interleukin-8 (IL-8) production. Similar impairment was observed upon treatment with mitochondrial function inhibitors. However, IL-8 secretion was not impaired in NIPSNAP1 and 2 individual knockout (KO) and double KO (DKO) cells. Moreover, the oxygen consumption rate (OCR) in mitochondria measured using a flex analyzer was significantly reduced in NIPSNAP1 or 2 KD cells, but not in DKO cells. CAM also dose-dependently reduced the OCR. These results indicate that CAM suppresses the IL-8 production via the mitochondrial quality control regulated by temporary functional inhibition of NIPSNAP1 and 2. Our findings provide new insight into the mechanisms underlying cytokine production, including the TLR-mitochondria axis, and the immunomodulatory effects of macrolides.

Immunomodulatory Effects of Macrolides Considering Evidence from Human and Veterinary Medicine.

Macrolide antimicrobial agents have been in clinical use for more than 60 years in both human and veterinary medicine. The discovery of the non-antimicrobial properties of macrolides and the effect of immunomodulation of the inflammatory response has benefited patients with chronic airway diseases and impacted morbidity and mortality. This review examines the evidence of antimicrobial and non-antimicrobial properties of macrolides in human and veterinary medicine with a focus toward veterinary macrolides but including important and relevant evidence from the human literature. The complete story for these complex and important molecules is continuing to be written.

Azithromycin Reduces Markers of Vascular Damage in Pediatric Patients With Sickle Cell Disease.

BackgroundImmunomodulatory effects of macrolides in chronic inflammation are well known. In this study, we tested our hypothesis that azithromycin (AZT) can decrease inflammation in pediatric patients with sickle cell disease (SCD).MethodsThe use of AZT as an anti-inflammatory agent was evaluated in double-blind, placebo-controlled, cross-over study for 8 weeks of treatment with 8 weeks of washout. Blood samples were collected before (PRE) and after (POST) each 8-week treatment period. Repeated measures analysis of variance (ANOVA) with post hoc multiple comparison procedures and Chi-square test were used for statistical analysis of the data. Complete blood count, distribution of the lymphocyte subsets, and plasma levels of markers of vascular damage were analyzed.ResultsA significant decrease in the number of leucocytes and granulocytes was observed in AZT group following treatment. An opposite dynamic was observed in placebo group; numbers of granulocytes significantly increased at POST interval. All markers of vascular damage were reduced in AZT group at POST interval with overall significance (P = 0.026). The most prominent significant changes were observed in levels of myeloid-related protein 8/14 (MRP8/14), lipocalin A (NGAL), matrix metalloproteinases (MMP) 9, and insulin-like growth factor-binding protein (IGFBP) 4. Plasma level of C-reactive protein (CRP) was significantly decreased in AZT group as well.ConclusionsData suggested that AZT may be beneficial in management of microvascular injury in SCD.

What is the evidence for macrolide therapy in chronic rhinosinusitis?

To assess the most recent evidence for macrolide therapy in chronic rhinosinusitis (CRS). Macrolides play a significant role in a select group of patients with CRS. Low-serum and tissue eosinophilia in patients who do not respond to corticosteroid therapy appeared to be an effective predictor of a CRS phenotype suitable for a trial of long-term macrolide therapy. Therapies using half a dose for longer than 12 weeks have noted good outcomes. The anti-inflammatory and immunomodulatory effects of macrolides have been demonstrated in several studies. Macrolides have shown an important role in patients who are nonresponsive to corticosteroid therapies, therefore patient selection is key. Previous inconsistencies in results may be due to poor patient selection.

18th International Congress of Pediatric Pulmonology Tokyo Chiba, June 27 - 30, 2019.

Pediatric PulmonologyVolume 54, Issue S1 p. S6-S6 ABSTRACTSFree Access Keynote Lecture First published: 27 June 2019 https://doi.org/10.1002/ppul.24369AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat 1 Macrolides – From Diffuse Pan-Bronchiolitis to CF and Beyond Bruce K. Rubin MEngr, MD, MBA, FRCPC Virginia Commonwealth University Department of Pediatrics and The Children’s Hospital of Richmond at VCU, Richmond, VA Email: bruce.rubin@vcuhealth.org The term “macrolide” describes drugs with a macrocyclic lactone ring of twelve or more elements. The nonantimicrobial properties of macrolides were suspected as far back as the 1960s, however their dramatic clinical effectiveness in treating diffuse panbronchiolitis has served to extend their use to a number of chronic inflammatory diseases including cystic fibrosis, non-CF bronchiectasis, chronic obstructive pulmonary disease, and chronic rhinosinusitis. Macrolide antibiotics administered in subantimicrobial doses improve pulmonary function and decrease exacerbation frequency for persons with bronchiectasis or cystic fibrosis. Data also suggest a beneficial effect of macrolide antibiotics in the treatment of steroid-dependent (neutrophil dominant) asthma and chronic obstructive pulmonary disease.1 The immunomodulatory effects of macrolides in patients with chronic inflammatory airway disease are independent of their antimicrobial properties and have been demonstrated in 14- and 15- (but not 16-) member macrolides that are devoid of antimicrobial activity. Immunomodulation, which differs from immunosuppression or anti-inflammation, is a nonlinear resetting of the immune response by modifying or regulating one or more functions of the immune system. We use the term immunomodulation to describe the downregulation of a hyperimmunity or hyperinflammation without impairing the normal immune or inflammatory response to defend against infection. Macrolides initially decrease, then increase, and have finally a sustained suppression of cytokine secretions from normal human bronchial epithelial cells through inhibition and activation of extracellular signal-regulated kinases (ERKs) and then reversibly retard cell proliferation probably through ERK. Macrolides are not anti-inflammatory but are true immunomodulators.2, 3 Consistent with this, macrolide antibiotics reduce mucin production as well as neutrophil migration by interfering with ERK signal transduction. Macrolides accumulate within cells, suggesting that they may associate with receptors or carriers responsible for the regulation of immune cell activities.4 Chronic macrolide use at low dosage as an immunomodulator drug will inevitably induce antimicrobial resistance. There are two principal forms of acquired macrolide resistance. Low level resistance or Mef, by far the most common, involves the activation of efflux pumps to drive the antibiotic out of the target cell. This can be overcome by higher doses of the drug and is reversible if antibiotic pressure is reversed. High level, or Erm, resistance involves an irreversible modification of the bacterial ribosome target. This is heritable and cannot be overcome by a higher concentration of drug.5 Other ERK inhibitors that can be administered as an aerosol are under development as novel therapy for neutrophil dominant airway disease.6 REFERENCES 1Rubin BK, Tamaoki J. Antibiotics as Anti-inflammatory and Immunomodulatory Agents. Basel. Birkhäuser Verlag AG; November 2004. 2Shinkai M, Foster GH, Rubin BK. Macrolide antibiotics modulate ERK phosphorylation and IL-8 and GM-CSF production by human bronchial epithelial cells. Am J Physiol Lung Cell Molec Physiol. 2006; 290: L75- L85. 3Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clinical Microbiol Rev. 2010; 23: 590- 615. 4Tanabe T, Kanoh S, Tsushima K, Yamazaki Y, Kubo K, Rubin BK. Clarithromycin inhibits interleukin-13-induced goblet cell hyperplasia in human airway cells. Am J Respir Cell Mol Biol. 2011; 45: 1075- 1083. 5Shinkai M, Rubin BK. Macrolides and airway inflammation in children. Pediatr Resp Rev. 2005; 6: 227- 235. 6Kanoh S, Tanabe T, Rubin BK. Dapsone inhibits IL-8 secretion from human bronchial epithelial cells stimulated with LPS and resolves airway inflammation in the ferret. Chest. 2011; 140: 980- 990. Volume54, IssueS1Supplement: 18th International Congress of Pediatric Pulmonology Tokyo Chiba, June 27 – 30, 2019June 2019Pages S6-S6 ReferencesRelatedInformation

The Immunomodulatory Effects of Macrolides-A Systematic Review of the Underlying Mechanisms.

The mechanisms underlying the non-antimicrobial immunomodulatory properties of macrolides are not well understood. To systematically review the evidence for the immunomodulatory properties of macrolides in humans and to describe the underlying mechanism and extent of their influence on the innate and adaptive immune system. A systematic literature search was done in MEDLINE using the OVID interface from 1946 to December 2016 according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA). Original articles investigating the influence of four macrolides (azithromycin, clarithromycin, erythromycin, and roxithromycin) on immunological markers in humans were included. We identified 22 randomized, controlled trials, 16 prospective cohort studies, and 8 case-control studies investigating 47 different immunological markers (186 measurements) in 1,834 participants. The most frequently reported outcomes were a decrease in the number of neutrophils, and the concentrations of neutrophil elastase, interleukin (IL)-8, IL-6, IL-1beta, tumor necrosis factor (TNF)-alpha, eosinophilic cationic protein, and matrix metalloproteinase 9. Inhibition of neutrophil function was reported more frequently than eosinophil function. A decrease in T helper (Th) 2 cells cytokines (IL-4, IL-5, IL-6) was reported more frequently than a decrease in Th1 cytokines (IL-2, INF-gamma). Macrolides influence a broad range of immunological mechanisms resulting in immunomodulatory effects. To optimize the treatment of chronic inflammatory diseases by macrolides, further studies are necessary, particularly comparing different macrolides and dose effect relationships.

Possible clinical effects of macrolides on the treatment of primary pulmonary mucosa-associated lymphoid tissue lymphoma

pulmonary nodules in left S and S were observed in December 2009 (Fig. 1d), CAM was increased to 400 mg/ day in January 2010. The nodules remained unchanged, and AZM (750 mg/week) was added to CAM (400 mg/ day) in November 2010, which subsequently decreased the nodules 2 months later (Fig. 1e). These findings in the left lower lobe were unchanged in December 2014 (Fig. 1f). Case 2: A 58-year-old Japanese woman with multiple cystic lesions (Fig. 1g) was diagnosed with p-MALToma in 2010. CAM (400 mg/day) was started in November 2010, and the chest CT findings remained unchanged for 2 years (Fig. 1h, i). CAM was discontinued at the patient’s request in May 2012; however, a pulmonary nodule in the left upper lobe was observed in May 2014, but increased in size over time (Fig. 1j). A bronchoscopic examination revealed lymphocytic inflammatory change, and she restarted CAM (400 mg/day) therapy in October 2014. The nodular lesion started to decrease in December 2014 (Fig. 1k) and nearly disappeared by May 2015 (Fig. 1l). The comprehensive mechanism of action of macrolides on MALToma remains unclear. However, among macrolides, AZM is more concentrated in cells, which may help to induce the apoptosis of T-lymphocytes that may be included in the pathogenesis and progression of MALToma, and anti-inflammatory and immunomodulatory effects of macrolides may also indirectly suppress tumor progression of p-MALToma. The clinical course of Case 1 may show the potential combined effects of CAM and AZM therapy. In addition, the long-term follow-up of Case 2 demonstrates the clinical suppressive effect of CAM on p-MALToma. In addition to rituximab monotherapy or use of this drug in combination with other agents, we think that macrolides represent a potentially beneficial alternative treatment choice of p-MALT lymphoma; however, further studies are needed to elucidate the most effective strategy for the treatment of p-MALToma. To the Editor,

Successful treatment of primary immune thrombocytopenia in aged patients using clarithromycin

Primary immune thrombocytopenia (ITP) is an autoimmune disease induced by autoantibodies against platelets. Helicobacter pylori is closely related to the pathogenesis of ITP, and recent studies have suggested that H. pylori-positive ITP can be successfully treated by eradication therapy against H. pylori. On the other hand, corticosteroids are the standard initial treatment for H. pylori-negative ITP patients. We have already reported three cases of ITP in which platelet counts increased following clarithromycin (CAM) treatment, irrespective of H. pylori infection status. In our previous report, the fact that platelet counts improved after CAM treatment suggested immunomodulatory effects of macrolides as well as antibacterial effects. Here, we report two cases of ITP successfully treated with CAM monotherapy. Case 1, a 75-year-old woman, was referred with purpura. The final diagnosis was H. pyloripositive ITP. The patient could not be treated with eradication therapy because of an allergy to penicillin. The patient was treated using CAM. The platelet count had increased from 1.6 10/mL to 6.0 10/mL after 4 weeks of CAM treatment (Fig. 1A). Case 2, a 77-year-old woman with H. pylori-negative ITP, was admitted with a gradual decrease in platelet count accompanied by purpura.

Immunomodulatory effects of macrolides during community-acquired pneumonia: a literature review

Macrolides are known to possess immunomodulatory properties, next to their antimicrobial effects. These immunomodulatory activities have been proven beneficial in chronic pulmonary inflammatory diseases. Whether macrolides also exert favourable immunomodulatory effects during acute inflammation, and therefore can act as adjuvant therapy in community-acquired pneumonia (CAP), is less clear. We aimed to give an overview of the existing evidence from in vitro and in vivo studies on the immunomodulatory effects of macrolides during CAP. A comprehensive search in the PubMed/MEDLINE and Embase databases was performed. Two investigators independently examined the eligible literature. Studies that dealt with the effects of macrolides on the immune response, in terms of cytokine secretion and the number or function of inflammatory and structural cells during acute inflammation, were included. A total of 27 studies were included, of which 15 were in vitro studies, 9 in vivo, 2 both in vivo and in vitro, and 1 was in human subjects. Although the methods and experimental model systems used in these studies are very heterogeneous, macrolides in general tempered inflammation caused by viable and non-viable bacteria or their products. Cytokine secretion decreased, as did inflammatory and structural cell activation and histological inflammatory signs. Not all data, however, are consistent and sometimes pro-inflammatory effects were found. To conclude, the available literature suggests that macrolides can temper the inflammatory response during CAP, independent of their antimicrobial activity. However, because the studies differ in their methodology, no definite conclusions can be drawn.

Azithromycin Treatment Modulates Cytokine Production in Chlamydia trachomatis Infected Women

Chlamydial infection of the lower genital tract usually spreads to the upper genital tract and is then responsible for more serious consequences of chlamydial infection, such as infertility, ectopic pregnancy, pelvic pain and pelvic inflammatory disease [1]. Genital infection with Chlamydia trachomatis and the resulting cytokine environment largely determines the outcome of infection and disease [2–7]. Chlamydial infections are usually treated with Azithromycin or Doxycycline [8]. The immunomodulatory effects of macrolides have mainly been shown in vitro or in animal experiments. It has been reported that macrolide antibiotics can interfere with cytokine production in vitro [9–11]. Azithromycin has also been reported to inhibit the production of pro-inflammatory cytokines [12–17]. There is little evidence from the clinical arena that these immunomodulatory actions of antibiotics play a role in terms of outcome. Therefore, further studies to investigate the potential usefulness of azithromycin are necessary to elucidate its mechanism of action. The direct relevance of these findings for the treatment of infectious and inflammatory diseases will have to be tested in patients. The results of clinical trials have suggested that antibacterial activity of azithromycin is efficacious in the treatment of chlamydial cervical infection [18–20]. However, there are no human studies that have assessed antibacterial as well as anti-inflammatory effects of azithromycin treatment in different clinical conditions associated with the chlamydial infections. In a recent study on a Macaque model, azithromycin effectively prevented the progression of inflammation and fibrosis in both the lower and upper reproductive tract after repeated chlamydial infections suggesting that azithromycin may provide anti-inflammatory as well as antimicrobial properties and this combined activity may be particularly well-suited for the treatment of chlamydial infection [21]. Therefore, it might be possible that in immunopathological conditions like infertility and pelvic inflammatory disease, the anti-inflammatory property of azithromycin may act in the eradication of infection and disease. Hence, in the present study in order to examine the anti-inflammatory effects of azithromycin, we investigated the levels of interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) in women representing different clinical conditions, that is, Chlamydiapositive fertile and infertile women with genital tract infection of C. trachomatis before and after treatment with azithromycin.

Helicobacter pylori eradication: Novel therapy for immune thrombocytopenic purpura? A review of the literature

Eradication of Helicobacter pylori (H. pylori ) from the gastric mucosa has been associated with improvement of several systemic diseases, including immune thrombocytopenic purpura (ITP). Over the last 5 years, several studies have reported improved platelet counts in H. pylori-positive ITP patients following standard triple H. pylori eradication therapy. Review of published studies in which eradication of H. pylori has been performed in the ITP population indicates an overall response rate of 52% in 193 subjects in whom H. pylori was eradicated. Cohorts from Japan and Italy report higher response rates. There is no established mechanism to explain how this organism, which does not invade the gastric mucosa, could be implicated in the pathogenesis of this immune-based platelet disorder. Several theories including molecular mimicry, platelet aggregation, and immunomodulatory effects of macrolides have been proposed to explain the platelet response to anti-H. pylori therapy. Large randomized-controlled studies enrolling patients from various ethnic backgrounds will be necessary to determine the response rate and mechanism of response and to gain a better understanding of the pathogenesis of ITP.

Optimal Pharmacological Therapy for Community-Acquired Pneumonia

The optimal pharmacological therapy of community-acquired pneumonia (CAP) is one of the most ardently debated issues in medicine. Presently, most guidelines recommend either a fluoroquinolone alone or dual therapy with a third-generation cephalosporin plus a macrolide in patients hospitalised with CAP, but few provide clinicians with specific considerations for selecting from these agents. Despite a similar spectrum of activity and favourable resistance patterns (for fluoroquinolones and third-generation cephalosporins) against CAP pathogens, there is emerging evidence that dual therapy may be superior to monotherapy in certain populations.In patients with non-severe CAP, the evidence supports the use of either monotherapy or dual therapy in most patients; however, patients with severe CAP or bacteraemic pneumococcal CAP experience improved survival when treated with dual therapy. It is unclear from this evidence if any specific combination of agents is the most effective, but the combination of a third-generation cephalosporin plus a macrolide is the most extensively studied. Dual therapy was superior to monotherapy irrespective of the susceptibility of the aetiological pathogen, thus insufficient antimicrobial spectrum does not explain the disparity. The most likely explanation for improved outcomes with dual therapy is the combined effect of optimised antimicrobial spectrum (including atypicals), decreased impact of resistance to a single agent and the immunomodulatory effects of macrolides. Increasing resistance in patients with non-severe CAP warrants the consideration of dual therapy and perhaps a reappraisal of agents usually reserved for second-line therapy, including doxycycline, in these populations as well. In light of the available evidence, dual therapy should be strongly considered in all patients with severe CAP, especially when complicated by pneumococcal bacteraemia.

Immunomodulatory effects of macrolides: Implications for practicing clinicians

Macrolides are regarded as the drugs of choice for the treatment of diffuse panbronchiolitis (DPB) due to their favorable effects on patient outcomes. These drugs decrease sputum production, thereby improving pulmonary function. Moreover, these effects are independent of dosing with respect to clarithromycin, erythromycin, and roxithromycin. The marked success of macrolides in this disease is a direct effect of impeding the inflammatory cascade. With their abilities to reduce the secretion of proinflammatory cytokines, ameliorate the infiltration of inflammatory cells into the airways, and reduce mucus secretion, macrolides are able to improve pulmonary function and quality of life in patients with chronic inflammatory diseases of the airways. Although prolonged use of macrolides raises concerns of increased adverse effects, data do not support such occurrences. With respect to concerns of resistance, it should be noted that in Japan, where macrolides are part of the treatment for DPB, these agents continue to be used effectively as antimicrobial agents. Therefore, the potential benefits of the immunomodulatory effects of macrolides in other conditions such as cystic fibrosis, chronic sinusitis, asthma, and chronic bronchitis are under investigation.

Preface [Hot Topic: Novel Immunomodulatory Effects of Macrolides in Inflammatory Lung Disease (Executive Editors: F. Martinez and T.J. Standiford)

Preface [Hot Topic: Novel Immunomodulatory Effects of Macrolides in Inflammatory Lung Disease (Executive Editors: F. Martinez and T.J. Standiford)