Nitric oxide‐releasing microparticles as a potent antimicrobial therapeutic against chronic rhinosinusitis bacterial isolates

Background

Bacteria, particularly in the biofilm state, may be implicated in the pathogenesis of chronic rhinosinusitis (CRS) and enhance antibiotic resistance. Nitric oxide (NO) is a gaseous immunomodulator with antimicrobial activity and a short half‐life, complicating achievement of therapeutic concentrations. We hypothesized that a novel microparticle‐based delivery platform, which allows for adjustable release of NO, could exhibit potent antibacterial effects.

Methods

Porous organosilica microparticles (SNO‐MP) containing nitrosylated thiol groups were formulated. Dissociation of the nitrosothiol groups generates NO at body temperature. The susceptibility of bacterial isolates from CRS patients to SNO‐MP was evaluated through a colony forming unit (CFU) assay. Serial dilutions of SNO‐MP in triplicate were incubated with isolates in suspension for 6 hours followed by plating on tryptic soy agar and overnight incubation followed by CFU quantification. Statistical analysis was performed with SPSS using one‐way analysis of variance with Bonferroni correction.

Results

SNO‐MP displayed antibacterial activity against gram‐positive (methicillin‐resistant and ‐sensitive Staphylococcus aureus) and gram‐negative (Pseudomonas aeruginosa, Enterobacter aerogenes, and Proteus mirabilis) isolates. SNO‐MP induced dose‐dependent reductions in CFU across all strains. Compared with controls and blank nanoparticles, SNO‐MP (10 mg/mL) induced a 99.99%‐100% reduction in CFU across all isolates, equivalent to a 5–9 log kill (p < 0.005). There was no statistically significant difference in CFU concentration between controls and blank microparticles.

Conclusion

SNO‐MP demonstrates potent bactericidal effect against antibiotic‐resistant CRS bacterial strains.

     

Role of Toll‐like receptor 9 signaling on activation of nasal polyp–derived fibroblasts and its association with nasal polypogenesis

Background

Nasal polyposis is characterized by persistent inflammation and remodeling in sinonasal mucosa. Toll‐like receptor 9 (TLR9) is a DNA receptor of the innate immune system that plays a pivotal role in fibrosis and inflammatory responses. The aim of this study is to explore the expression, activity, and potential pathogenic role of TLR9 signaling in tissue remodeling in nasal polyp–derived fibroblasts (NPDFs).

Methods

Fibrotic and inflammatory responses elicited by type A CpG oligonucleotides were examined in the NPDFs by a combination of real‐time quantitative polymerase chain reaction, Western blot analysis, enzyme‐linked immunosorbent assay, and immunofluorescence staining. For these experiments, the NPDFs were stimulated with different TLR9 agonists (CpG A and B) and blocked with inhibitors (MyD88 inhibitor and chloroquine).

Results

TLR9 expression was significantly higher in nasal polyposis (NP) tissues compared to control or chronic rhinosinusitis (CRS) mucosa. In the NPDFs, TLR9 showed intracellular localization and expression of TLR9 was increased after treatment with CpG A. CpG A increased production of α‐smooth muscle actin (α‐SMA), fibronectin, and matrix metalloproteinases (MMPs) (MMP1, MMP2, and MMP9) in the NPDFs, while MyD88 inhibitor and chloroquine, which are known to block the TLR9 signaling pathway, inhibited their production. CpG A also produced type I interferons (IFN‐α and IFN‐β), which were inhibited by MyD88 inhibitor.

Conclusion

Our data indicates that CpG A–induced fibroblast activation and cytokine production were mediated via TLR9 stimulation in NPDFs. Disrupting this process with an inhibitor targeting TLR9 or its downstream signaling pathways could represent a novel approach to CRS with NP (CRSwNP) therapy.

     

Efficacy of nasal irrigation with 200 μg/mL amphotericin B after functional endoscopic sinus surgery: a randomized,placebo‐controlled,double‐blind study

Background

Previous studies have shown controversial results of topical amphotericin B (AMB) nasal irrigation for chronic rhinosinusitis (CRS). The purpose of this study was to evaluate the efficacy of 200 μg/mL AMB nasal irrigation as an adjuvant therapy after functional endoscopic sinus surgery (FESS).

Methods

Patients with CRS who had received FESS for treatment were recruited and assigned to 1 of 2 groups at random at 1 month postsurgery. In the AMB group patients received nasal irrigation with 200 μg/mL of AMB for 2 months on a daily basis. In the control group normal saline irrigation was given instead. Before FESS and before and after nasal irrigation, patients’ sinonasal symptoms were assessed through a questionnaire that was a Taiwanese version of the 22‐item Sino‐Nasal Outcome Test (TWSNOT‐22). In addition, patients received endoscopic examination, acoustic rhinometry, smell test, saccharine transit test, and bacterial cultures obtained from their middle meati.

Results

A total of 73 patients completed the study between December 2014 and January 2017. Among them, 37 received nasal irrigation with AMB solution, and 36 with saline. In the AMB group, scores of TWSNOT‐22 dropped significantly after irrigation compared with before (p = 0.005). In the control group, TWSNOT‐22 scores did not changed after irrigation (p = 0.451). However, there were no significant differences in TWSNOT‐22, endoscopic score, smell test, saccharine transit test, and bacterial culture rate after irrigation between 2 groups.

Conclusion

Our study showed that in post‐FESS care, nasal irrigation with 200 μg/mL of AMB did not provide additional benefit compared with saline irrigation.     

Lack of additional effects of long‐term,low‐dose clarithromycin combined treatment compared with topical steroids alone for chronic rhinosinusitis in China: a randomized,controlled trial

Background

In China, clarithromycin is considered an effective treatment option for chronic rhinosinusitis (CRS) due to its unique immunopathologic characteristics. Our study's aim was to determine whether a topical steroid and clarithromycin combination is better than a single topical steroid for Chinese patients with CRS.

Methods

Patients with CRS with/without nasal polyps were included in this study and randomly assigned to a clarithromycin plus budesonide aqua nasal spray group (CLM + BUD, clarithromycin 0.25 g/d and budesonide 256 μg/d) or a budesonide‐alone group (BUD, budesonide 256 μg/d). The treatment period was 3 months. The primary outcome was visual analog scale (VAS) score for 5 major symptoms and a general nasal symptom. Other assessments included the 22‐item Sino‐Nasal Outcome Test (SNOT‐22), computed tomography scan (Lund‐Mackay score), and rigid nasal endoscopy (Lund‐Kennedy score). Nasal secretion evaluation was the secondary outcome.

Results

Seventy‐four patients were included and randomly assigned to the CLM + BUD group (n = 38) or the BUD group (n = 36). VAS scores for nasal obstruction, rhinorrhea, smell reduction, headache, nasal pain, and general nasal symptom were markedly improved in both treatment arms, but the differences between groups were not significant. Furthermore, SNOT‐22, Lund‐Mackay, and Lund‐Kennedy scores improved significantly after treatment in both groups, and were slightly better in the CLM + BUD group. For the responders in the CLM + BUD group, interleukin (IL)‐6 and IL‐8 were markedly reduced.

Conclusion

The combination of CLM + BUD for the treatment of first‐time‐diagnosed CRS in this Chinese population cohort did not show a better effect compared with a single BUD regimen, but it may have a better effect in some patients with increased IL‐6 or IL‐8.