Effects of salbutamol and phlorizin on acute pulmonary inflammation and disease severity in experimental sepsis

Abstract

Respiratory infection can be exacerbated by the high glucose concentration in the airway surface liquid (ASL). We investigated the effects of salbutamol and phlorizin on the pulmonary function, oxidative stress levels and SGLT1 activity in lung, pulmonary histopathological damages and survival rates of rats with sepsis. Sepsis was induced by cecal ligation and puncture surgery (CLP). Twenty-four hours after surgery, CLP rats were intranasally treated with saline, salbutamol or phlorizin. After 2 hours, animals were anesthetized and sacrificed. Sepsis promoted atelectasis and bronchial inflammation, and led to increased expression of SGLT1 on cytoplasm of pneumocytes. Salbutamol treatment reduced bronchial inflammation and promoted hyperinsuflation in CLP rats. The interferon-ɤ and Interleucin-1β concentrations in bronchoalveolar lavage (BAL) were closely related to the bronchial inflammation regulation. Salbutamol stimulated SGLT1 in plasma membrane; whereas, phlorizin promoted the increase of SGLT1 in cytoplasm. Phlorizin reduced catalase activity and induced a significant decrease in the survival rate of CLP rats. Taken together, sepsis promoted atelectasis and lung inflammation, which can be associated with SGLT1 inhibition. The loss of function of SGLT1 by phlorizin are related to the augmented disease severity, increased atelectasis, bronchial inflammation and a significant reduction of survival rate of CLP rats. Alternatively salbutamol reduced BAL inflammatory cytokines, bronchial inflammation, atelectasis, and airway damage in sepsis. These data suggest that this selective β2-adrenergic agonist may protect lung of septic acute effects.

Rescuable effect of R-salbutamol in LPS-induced immune dysfunction of sepsis

“…A growing body of evidences have revealed the effects of β2-agonists on possessing anti-inflammatory properties on airways and reducing pro-inflammatory mediators as well as preventing tissue oedema and exudate. Despite sufficient researches have demonstrated the compelling protective effects of salbutamol and other β2-agonists on preventing sepsis in pre-clinical experiments, these agents have not been shown to improve outcomes in clinical trials in ARDS (a syndrome in critically ill sepsis)[26][27]. As we acknowledged, two enantiomers of salbutamol exhibit differential pharmacological effects.…”

Pathophysiology of SARS-CoV-2 in Lung of Diabetic Patients

“…We also have previously demonstrated the increase of ASL glucose concentration promoted by SGLT1 inhibitors in the lungs of diabetic animals ( Oliveira et al, 2016 ); however, the opposite effect on ASL glucose concentration was observed under the beta-adrenergic agonist application due to the SGLT1 translocation to plasma membrane of type I and type II pneumocytes. In this context, we also showed that SGLT1 inhibitors promote bronchial inflammation (interferon-γ and Interleucin-1β), reduction on antioxidant system, and atelectasis associated with significant decrease in survival rate in an ARDS promoted by cecum ligation and puncture (CLP)-induced sepsis animal model ( Cardoso-Sousa et al, 2019 ). Otherwise, a specific β2-adrenergic agonist reduced bronchial inflammation (interleucin-1β), preserved higher levels of antioxidant system, and reduced pulmonary atelectasis associated with bronchodilation ( Cardoso-Sousa et al, 2019 ).…”

“…In this context, we also showed that SGLT1 inhibitors promote bronchial inflammation (interferon-γ and Interleucin-1β), reduction on antioxidant system, and atelectasis associated with significant decrease in survival rate in an ARDS promoted by cecum ligation and puncture (CLP)-induced sepsis animal model ( Cardoso-Sousa et al, 2019 ). Otherwise, a specific β2-adrenergic agonist reduced bronchial inflammation (interleucin-1β), preserved higher levels of antioxidant system, and reduced pulmonary atelectasis associated with bronchodilation ( Cardoso-Sousa et al, 2019 ). The SGLT1-triggered water transport is feasible directly together with classical Na + and glucose transport, and also indirectly as a powerful facilitator of passive water cotransport ( Erokhova et al, 2016 ).…”

“…In moderate and severe fluxes of this protein-rich exudate biofluid, the compensatory ventilatory response can be inefficient to maintain adequate exudate O 2 and CO 2 exchanges ( Oliveira et al, 2016 ). Considering the resemblance between inflammatory response in the lung of patients with COVID-19 and sepsis ( Tomar et al, 2020 ), it is expected that SGLT1 is also reduced in luminal membrane of pneumocytes ( Cardoso-Sousa et al, 2019 ), which can resonate in ASL glucose concentration and ASL volume repercussion. Additional effort needs to be expended to raise this question.…”

Intestinal SGLT1 as a therapeutic target in COVID‐19‐related diabetes: A “two‐edged sword” hypothesis

“…6 In support of the perspective that SGLT1 might be implicated in the metabolic disarrangement observed in some patients with COVID-19, Dai et al 10 phlorizin was correlated with a decreased survival rate in a rat model of bronchial inflammation and sepsis. 12 SGLT activation has recently been a key therapeutic target in T2D, where excessive glucose reabsorption by the kidneys is observed. 13 Available drugs mainly inhibit SGLT2, located in the early segment of the proximal renal tube, thus leading to reduced renal glucose reabsorption.…”