The nitroxyl donor Angeli's salt ameliorates Staphylococcus aureus-induced septic arthritis in mice

Abstract

Septic arthritis is a severe and rapidly debilitating disease associated with severe joint pain, inflammation and oxidative stress. Nitroxyl (HNO) has become a nitrogen oxide of significant interest due to its pharmacological endpoints that are potentially favorable for treating varied diseases. However, whether HNO also serves as a treatment to septic arthritis is currently unknown. The aim of this study was to investigate the effect of the HNO donor, Angeli's salt (AS), in the outcome of chronic Staphylococcus aureus (S. aureus)-induced septic arthritis in mice. Daily treatment with AS inhibited mechanical hyperalgesia and inflammation (edema, leukocyte migration, cytokines release and NF-κB activation, and oxidative stress) resulting in reduced disease severity (clinical course, histopathological changes, proteoglycan levels in the joints, and osteoclastogenesis). In addition, AS decreased the number of S. aureus colony forming unities in synovial tissue, enhanced the bactericidal effect of macrophages and inhibited the worsening of systemic inflammatory response (leukocyte counts in the lung and systemic proinflammatory cytokine concentration). Our results suggest for the first time the therapeutic potential of AS in a model of septic arthritis by mechanisms involving microbicidal effects, anti-inflammatory actions and reduction of disease severity.

15d-PGJ2-loaded nanocapsules ameliorate experimental gout arthritis by reducing pain and inflammation in a PPAR-gamma-sensitive manner in mice

“…Mechanistically, 15d-PGJ 2 activates PPAR-γ that induces the hyperpolarization of nociceptor neurons by activating the NO/cGMP/K + ATP channels signaling pathway through the release of β-endorphin 34 , 35 . In fact, activation of this signaling pathway is a mechanism by which morphine 36 , dypirone 37 , nitroxyl donor Angeli’s salt 38 , and some flavonoids such as diosmin 39 and naringenin 40 produce analgesic effect. Thus, this mechanism contributes to the analgesic properties of 15d-PGJ 2 .…”

Interleukin-33 Receptor (ST2) Deficiency Improves the Outcome of Staphylococcus aureus-Induced Septic Arthritis

“…Infectious disease is the outcome of an intense crosstalk between invading pathogen and host defense armory ( 58 ). In septic arthritis, the synovial membrane inflammation leads to tissue destruction and dysfunction, resulting into significant painful condition and morbidity ( 28 , 56 , 59 ). In this context, the effect of ST2 deficiency in staphylococcal arthritis was evident since the first day after bacteria injection, inducing articular hyperalgesia, edema and a focal collection of immune cells that secret proinflammatory mediators such as TNF-α and IL-1β, which in turn contribute to the knee joint lesion, abscess and function loss ( 28 ).…”

“…injection of 10 µl of sterile saline was used as negative control group. To assess the intensity of arthritis, a clinical score was carried out using macroscopic inspection of the knee joints yielding a score of 0–4 for each limb (0—normal, 1—periarticular erythema, 2—articular erythema and edema, 3—function loss with difficult locomotion and articular extension, 4—purulent process with abscess formation) ( 28 ).…”

“…Septic arthritis is considered as one of the most aggressive joint diseases due to its rapidly progressive disease profile, pain, severe joint lesion, and dysfunction even with therapy onset ( 27 , 28 ). Patients with underlying joint diseases, such as RA are 4- to 15-fold more susceptible to septic arthritis than general population ( 29 ).…”

“…S. aureus is the most common cause of SA ( 31 ). There is evidence that both drug resistant S. aureus such as methicillin-resistant S. aureus and non-drug resistant S. aureus cause septic arthritis ( 28 , 29 , 33 , 34 ). The fast development of joint destruction in septic arthritis supports the urgent need for development of new treatment strategies against S. aureus arthritis.…”