Abstract
IntroductionThe lack of effective anti-inflammatory therapies for pneumonia represents a challenge for identifying new alternatives. Non-digestible galacto-oligosaccharides (GOS) are attractive candidates due to their anti-inflammatory and immunomodulatory effects both locally and systemically. ObjectivesThe anti-inflammatory properties of GOS were investigated in calves with lung infections and in calf primary bronchial epithelial cells (PBECs) and human lung epithelial cells (A549). To delineate the mechanism, the potential capacity of GOS to inhibit the NLR family pyrin domain containing 3 (NLRP3) inflammasome has been investigated. MethodsGOS were administrated orally to calves with naturally occurring lung infections during early life or used as pretreatments in cell cultures exposed to M. haemolytica, lipopolysaccharides (LPS), leukotoxin or ATP. The cell composition, cytokine/chemokine concentrations, and M. haemolytica-LPS lgG levels in broncho-alveolar lavage fluid (BALF) and blood were investigated, while the M. haemolytica positivity in BALF and bronchial mucosa was detected in vivo. Key markers of NLRP3 inflammasome activation were measured in vivo and in vitro. ResultsGOS reduced M. haemolytica positivity and M. haemolytica-LPS lgG levels in calves with lung infections. Regulation of immune function and suppression of inflammatory response by GOS is related to the inhibition of NLRP3 inflammasome as observed in bronchial mucosal tissue of infected calves. The M. haemolytica-induced IL-1β production in PBECs was lowered by GOS, which was associated with NLRP3 inflammasome inhibition caused by the decreased reactive oxygen species and ATP production. GOS inhibited leukotoxin-induced ATP production in PBECs. The LPS- and ATP-induced NLRP3 inflammasome activation in PBECs and A549 cells was suppressed by GOS. ConclusionGOS exert anti-inflammatory properties by inhibiting the NLRP3 inflammasome activation in vitro and in vivo, suggesting a potential role for GOS in the prevention of lung infections.
Highlights
The lack of effective anti-inflammatory therapies for pneumonia represents a challenge for identifying new alternatives
We investigated whether GOS would alleviate airway inflammation in calves with lung infections and tried to unravel the mechanism by using in vitro systems with calf primary bronchial epithelial cells (PBECs) and human lung epithelial cells stimulated with M. haemolytica/LPS/adenosine triphosphate (ATP)
The clinical scores increased significantly over time with the peak at week 6 (Fig. 1D). These findings indicate that lung infections are present in these calves from week 5
Summary
The lack of effective anti-inflammatory therapies for pneumonia represents a challenge for identifying new alternatives. The cell composition, cytokine/chemokine concentrations, and M. haemolytica-LPS lgG levels in broncho-alveolar lavage fluid (BALF) and blood were investigated, while the M. haemolytica positivity in BALF and bronchial mucosa was detected in vivo. Regulation of immune function and suppression of inflammatory response by GOS is related to the inhibition of NLRP3 inflammasome as observed in bronchial mucosal tissue of infected calves. Lung epithelial cells detect inhaled pathogens through ample pattern-recognition receptors, such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) [6]. These receptors can recognize virulence factors of pathogens, for example, M. haemolytica can release lipopolysaccharides (LPS) to activate TLR4 [3]. Antibiotics remain the mainstay for the treatment of lung infections
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