Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media

Khomtchouk, Kelly; Joseph, Lein; Khomtchouk, Bohdan B.; Kouhi, Ali; Massa, Solange; Xia, Anping; Koliesnik, Ievgen; Pletzer, Daniel; Bollyky, Paul L.; Maria, Peter L. Santa

doi:10.1038/s41522-021-00200-z

Cited by 12 publications

(6 citation statements)

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“…Topical fluoroquinolones effectively convert active disease to inactive but, by mechanism, do not address persister cells, which are the key drivers of CSOM recurrence. 42-44 However, these findings are limited by possible selection bias, as patients at a tertiary center likely represent the more severe spectrum of disease. We aimed to account for this by not setting a minimum follow-up time for medical outcomes and analyzing if prior surgery influenced outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, patients who were otorrhea free at the most recent visit had episodes of otorrhea at earlier visits and may develop recurrent otorrhea at future visits, suggesting even poorer results. Topical fluoroquinolones effectively convert active disease to inactive but, by mechanism, do not address persister cells, which are the key drivers of CSOM recurrence 42‐44 . However, these findings are limited by possible selection bias, as patients at a tertiary center likely represent the more severe spectrum of disease.…”

Section: Discussionmentioning

confidence: 99%

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Long‐Term Health Utilization and Outcomes in Chronic Suppurative Otitis Media

Thai¹,

Aaron²,

Kaufman³

et al. 2021

Otolaryngol.--head neck surg.

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Objective To report health utilization patterns and outcomes of medical and surgical management in patients with chronic suppurative otitis media (CSOM). Study Design Retrospective cohort. Setting Academic otology clinic. Methods This study included 175 patients with CSOM with a first clinic visit at our institution between March 2011 and November 2016. All patients displayed a diagnosis of CSOM by International Classification of Diseases code, had at least 1 episode of active CSOM (defined as perforation with otorrhea), and had a documented history of chronic ear infections. The mean age was 49.5 ± 1.5 years, 53% were female, and mean follow-up time was 3.5 ± 0.3 years. Results Patients had an average of 9.5 ± 0.5 otology visits, 4.7 ± 0.4 prescriptions, and 1.7 ± 0.1 surgeries, with estimated per patient cost ranging from $3927 to $20,776. Under medical management, 69% of patients displayed recurrence of disease, with a median time to recurrence of 4 months. For tympanoplasty and tympanomastoidectomy, median time to recurrence was similar at 5 and 7 years, respectively ( P = .73). At the most recent visit, the prevalence of all patients with CSOM displaying moderate or worse sensorineural hearing loss (SNHL) was 41%. Conclusions CSOM represents a major public health issue with high health care utilization and associated costs. Surgery is superior to medical therapy for achieving short- to medium-term inactive disease. Patients with CSOM display a high SNHL burden.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long‐Term Health Utilization and Outcomes in Chronic Suppurative Otitis Media

Thai¹,

Aaron²,

Kaufman³

et al. 2021

Otolaryngol.--head neck surg.

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“…3C, D and S3). Ly6G + cell recruitment in the lungs, which is associated with neutrophil levels (37), was also measured, since neutrophils have been reported to serve an important role in lung injury (38). Immunohistochemical staining results indicated that the number of Ly6G + cells was significantly increased in the SAP group compared with in the Sham group, and this was then significantly decreased by emodin or DEX treatment (Fig.…”

Section: Emodin and Dex Decrease Apoptosis In The Lungs During Sap Progressionmentioning

confidence: 98%

Emodin ameliorates acute pancreatitis‑induced lung injury by suppressing NLRP3 inflammasome‑mediated neutrophil recruitment

Jiang

Luo

et al. 2021

Exp Ther Med

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Severe acute pancreatitis (SAP) activates the systemic inflammatory response and is potentially lethal. The aim of the present study was to determine the effects of emodin on acute lung injury (ALI) in rats with SAP and investigate the role of the Nod-like receptor protein 3 (NLRP3) inflammasome and its association with neutrophil recruitment. Sodium taurocholate (5.0%) was used to establish the SAP model. All animals were randomly assigned into four groups: Sham, SAP, emodin and dexamethasone (positive control drug) groups (n=10 mice per group). Histopathology observation of pancreatic and lung tissues was detected by hematoxylin and eosin staining. The levels of serum amylase, IL-1β and IL-18 were measured by ELISA. Single-cell suspensions were obtained from enzymatically digested lung tissues, followed by flow cytometric analysis for apoptosis. In addition, the expression levels of NLRP3 inflammasome-associated and apoptosis-associated proteins in lung tissues were measured by western blotting. Moreover, lymphocyte antigen 6 complex locus G6D + (Ly6G + ) cell recruitment was detected using immunohistochemical analysis. The results revealed that emodin markedly improved pancreatic histological injury and decreased the levels of serum amylase, IL-1β and IL-18. Pulmonary edema and apoptosis were significantly alleviated by emodin. Additionally, the protein expression levels of intercellular adhesion molecule 1, NLRP3, apoptosis-associated speck-like protein containing a CARD and cleaved caspase-1 were downregulated following emodin treatment. Moreover, emodin inhibited Ly6G + cell recruitment in lung tissues. The present study demonstrated that emodin may offer protection against ALI induced by SAP via inhibiting and suppressing NLRP3 inflammasome-mediated neutrophil recruitment and may be a novel therapeutic strategy for the clinical treatment of ALI.

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“…Neutrophils are responsible for both host defense and host tissue damage in the early phase of bacterial infections particularly in CSOM [ 25 ]. We have previously identified that neutrophils were the most abundant cell type in CSOM middle ear effusions using Ly6G/C, a surface marker of mature neutrophils, by multi-parameter flow cytometry (FCM) analysis [ 25 ]. In the current study, we performed immunostaining with the Ly6G/C antibody to assess neutrophil presence in the cochlea.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, immune cell-mediated damage might explain our findings in this model of CSOM. We and others previously showed that CSOM contains a predominance of neutrophils in the middle ear [ 3 , 25 , 43 ]. This current study showed a paucity of neutrophils in the inner ear and the timing observing these neutrophils was not in keeping with the observed OHC loss, ruling this cell out as the main driver for SNHL in CSOM.…”

Section: Discussionmentioning

confidence: 99%

Chronic suppurative otitis media causes macrophage-associated sensorineural hearing loss

Xia

Thai

Cao

et al. 2022

J Neuroinflammation

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Background Chronic suppurative otitis media (CSOM) is the most common cause of permanent hearing loss in children in the developing world. A large component of the permanent hearing loss is sensory in nature and our understanding of the mechanism of this has so far been limited to post-mortem human specimens or acute infection models that are not representative of human CSOM. In this report, we assess cochlear injury in a validated Pseudomonas aeruginosa (PA) CSOM mouse model. Methods We generated persisters (PCs) and inoculated them into the mouse middle ear cavity. We tracked infection with IVIS and detected PA using RT-PCR. We assessed cochlear damage and innate immunity by Immunohistochemistry. Finally, we evaluated cytokines with multiplex assay and quantitative real-time PCR. Results We observed outer hair cell (OHC) loss predominantly in the basal turn of the cochlear at 14 days after bacterial inoculation. Macrophages, not neutrophils are the major immune cells in the cochlea in CSOM displaying increased numbers and a distribution correlated with the observed cochlear injury. The progression of the morphological changes suggests a transition from monocytes into tissue macrophages following infection. We also show that PA do not enter the cochlea and live bacteria are required for cochlear injury. We characterized cytokine activity in the CSOM cochlea. Conclusions Taken together, this data shows a critical role for macrophages in CSOM-mediated sensorineural hearing loss (SNHL).

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Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media

Cited by 12 publications

References 50 publications

Long‐Term Health Utilization and Outcomes in Chronic Suppurative Otitis Media

Long‐Term Health Utilization and Outcomes in Chronic Suppurative Otitis Media

Emodin ameliorates acute pancreatitis‑induced lung injury by suppressing NLRP3 inflammasome‑mediated neutrophil recruitment

Chronic suppurative otitis media causes macrophage-associated sensorineural hearing loss

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