Evidence for Na+–glucose cotransporter in type I alveolar epithelium

Bodega, Francesca; Sironi, Chiara; Armilli, Marta; Porta, Cristina; Agostoni, Emilio

doi:10.1007/s00418-010-0725-7

Cited by 9 publications

(6 citation statements)

References 23 publications

(39 reference statements)

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“…In the well‐characterized perfused, fluid‐filled rat lung model, we found that dapagliflozin had no adverse effects on fluid absorption or lung glucose concentrations. The SGLT1 isoform is expressed in alveolar epithelium, where it contributes to sodium, glucose and fluid absorption (Bodega et al, ). Phlorizin, an inhibitor of SGLT1/2, reduced lung liquid and glucose absorption, increasing luminal glucose concentrations with potential adverse effects of pulmonary oedema and increased bacterial proliferation (Oliveira et al, ).…”

Section: Discussionmentioning

confidence: 99%

Dapagliflozin‐lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice

Åstrand

Wingren

Benjamin

et al. 2017

British J Pharmacology

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Background and PurposeHyperglycaemia increases glucose concentrations in airway surface liquid and increases the risk of pulmonary Pseudomonas aeruginosa infection. We determined whether reduction of blood and airway glucose concentrations by the anti‐diabetic drug dapagliflozin could reduce P. aeruginosa growth/survival in the lungs of diabetic mice.Experimental ApproachThe effect of dapagliflozin on blood and airway glucose concentration, the inflammatory response and infection were investigated in C57BL/6J (wild type, WT) or leptin receptor‐deficient (db/db) mice, treated orally with dapagliflozin prior to intranasal dosing with LPS or inoculation with P. aeruginosa. Pulmonary glucose transport and fluid absorption were investigated in Wistar rats using the perfused fluid‐filled lung technique.Key ResultsFasting blood, airway glucose and lactate concentrations were elevated in the db/db mouse lung. LPS challenge increased inflammatory cells in bronchoalveolar lavage fluid from WT and db/db mice with and without dapagliflozin treatment. P. aeruginosa colony‐forming units (CFU) were increased in db/db lungs. Pretreatment with dapagliflozin reduced blood and bronchoalveolar lavage glucose concentrations and P. aeruginosa CFU in db/db mice towards those seen in WT. Dapagliflozin had no adverse effects on the inflammatory response in the mouse or pulmonary glucose transport or fluid absorption in the rat lung.Conclusion and ImplicationsPharmacological lowering of blood glucose with dapagliflozin effectively reduced P. aeruginosa infection in the lungs of diabetic mice and had no adverse pulmonary effects in the rat. Dapagliflozin has potential to reduce the use, or augment the effect, of antimicrobials in the prevention or treatment of pulmonary infection.

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Section: Discussionmentioning

confidence: 99%

Dapagliflozin‐lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice

Åstrand

Wingren

Benjamin

et al. 2017

British J Pharmacology

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“…BODEGA et al [61] recently identified SGLT protein in type I and II alveolar cells of rat and sheep lung. However, SGLT1 protein could not be detected in adult rabbit lung tissue.…”

Section: Glucose Transport In Distal Lung Epitheliummentioning

confidence: 99%

Sweet talk: insights into the nature and importance of glucose transport in lung epithelium

2012

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For over 50 years, glucose has been recognised to cross the lung epithelial barrier and be transported by lung epithelial cells. However, until recently, research into these processes focused on their effects on lung liquid volume. Here, we consider a newly identified role for pulmonary glucose transport in maintaining low airway surface liquid (ASL) glucose concentrations and propose that this contributes to lung defence against infection.Glucose diffuses into ASL via paracellular pathways at a rate determined by paracellular permeability and the transepithelial glucose gradient. Glucose is removed from ASL in proximal airways via facilitative glucose transporters, down a concentration gradient generated by intracellular glucose metabolism. In the distal lung, glucose transport via sodium-coupled glucose transporters predominates. These processes vary between species but universally maintain ASL glucose at 3-20-fold lower concentrations than plasma.ASL glucose concentrations are increased in respiratory disease and by hyperglycaemia. Elevated ASL glucose in intensive care patients was associated with increased Staphylococcus aureus infection. Diabetic patients with and without chronic lung disease are at increased risk of respiratory infection. Understanding of mechanisms underlying lung glucose homeostasis could identify new therapeutic targets for control of ASL glucose and prevention and treatment of lung infection.

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“…Additionally, the SLC5A1 mRNA has also been identified in distal lung epithelium of animal and human epithelium 1 10 11 12 . The SGLT1 protein has been described on the surface of type I 13 and type II 14 pneumocytes. The instillation of phlorizin, an inhibitor of SGLT1 cotransporter, decreased glucose reabsorption in rat lung in situ under normoglycemic conditions 15 , suggesting an important role of SGLT1 in ASL glucose homeostasis.…”

mentioning

confidence: 99%

SGLT1 activity in lung alveolar cells of diabetic rats modulates airway surface liquid glucose concentration and bacterial proliferation

Oliveira

Candeia-Medeiros

Cavalcante-Araújo

et al. 2016

Sci Rep

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High glucose concentration in the airway surface liquid (ASL) is an important feature of diabetes that predisposes to respiratory infections. We investigated the role of alveolar epithelial SGLT1 activity on ASL glucose concentration and bacterial proliferation. Non-diabetic and diabetic rats were intranasally treated with saline, isoproterenol (to increase SGLT1 activity) or phlorizin (to decrease SGLT1 activity); 2 hours later, glucose concentration and bacterial proliferation (methicillin-resistant Sthaphylococcus aureus, MRSA and Pseudomonas aeruginosa, P. aeruginosa) were analyzed in bronchoalveolar lavage (BAL); and alveolar SGLT1 was analyzed by immunohistochemistry. BAL glucose concentration and bacterial proliferation increased in diabetic animals: isoproterenol stimulated SGLT1 migration to luminal membrane, and reduced (50%) the BAL glucose concentration; whereas phlorizin increased the BAL glucose concentration (100%). These regulations were accompanied by parallel changes of in vitro MRSA and P. aeruginosa proliferation in BAL (r = 0.9651 and r = 0.9613, respectively, Pearson correlation). The same regulations were observed in in vivo P. aeruginosa proliferation. In summary, the results indicate a relationship among SGLT1 activity, ASL glucose concentration and pulmonary bacterial proliferation. Besides, the study highlights that, in situations of pulmonary infection risk, such as in diabetic subjects, increased SGLT1 activity may prevent bacterial proliferation whereas decreased SGLT1 activity can exacerbate it.

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Evidence for Na+–glucose cotransporter in type I alveolar epithelium

Cited by 9 publications

References 23 publications

Dapagliflozin‐lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice

Dapagliflozin‐lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice

Sweet talk: insights into the nature and importance of glucose transport in lung epithelium

SGLT1 activity in lung alveolar cells of diabetic rats modulates airway surface liquid glucose concentration and bacterial proliferation

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