Impacts of peroxisome proliferator-activated receptor-γ activation on cigarette smoke-induced exacerbated response to bacteria

Abstract

Chronic obstructive pulmonary disease (COPD) is characterised by a state of chronic pulmonary inflammation punctuated by microbial exacerbations. Despite advances in treatment options, COPD remains difficult to manage. In this study, we investigated the potential of peroxisome proliferator-activated receptor (PPAR)γ activation as a new therapy against cigarette smoke-induced inflammation and its associated bacterial exacerbation. C57BL/6 mice were exposed to room air or cigarette smoke for either 4 days or 4 weeks and treated either prophylactically or therapeutically with rosiglitazone. The impact of rosiglitazone on cigarette smoke-induced exacerbated response to the bacterial pathogen nontypeable Haemophilus influenzae (NTHi) was studied using the therapeutic treatment protocol. We found that rosiglitazone was able to reduce cigarette smoke-induced neutrophilia both when administered prophylactically or therapeutically. Therapeutic intervention with rosiglitazone was also effective in preventing cigarette smoke-induced neutrophilia exacerbation following NTHi infection. Moreover, the anti-inflammatory effects of rosiglitazone did not lead to an increase in the pulmonary bacterial burden, unlike dexamethasone. Altogether, our data suggest that pharmacological activation of PPARγ may be an effective therapeutic approach to improve COPD management, as it is able to reduce cigarette smoke-induced inflammation and decrease the magnitude of bacterial exacerbations, without compromising the ability of the immune system to control the infection.

PPARγand the Innate Immune System Mediate the Resolution of Inflammation

“…Another report showed treatment with rosiglitazone, both prophylactically and therapeutically, reduced inflammatory cell counts in the bronchoalveolar lavage fluid in response to four weeks of cigarette exposure. However, inflammatory mediator levels were only reduced with prophylactic treatment, suggesting that the therapeutic effects of PPAR γ may be independent of changes in inflammatory mediators [ 134 ]. When an exacerbatory infection with nontypeable Haemophilus influenzae was added, rosiglitazone reduced neutrophil influx into the lung without compromising bacterial clearance, though no differences in the inflammatory signal IL-1 α , MCP-1, or CXCL5 were detected in the BALF, further supporting the concept that PPAR γ therapeutic effects are not due to simply regulating inflammatory mediator production [ 134 ].…”

“…However, inflammatory mediator levels were only reduced with prophylactic treatment, suggesting that the therapeutic effects of PPAR γ may be independent of changes in inflammatory mediators [ 134 ]. When an exacerbatory infection with nontypeable Haemophilus influenzae was added, rosiglitazone reduced neutrophil influx into the lung without compromising bacterial clearance, though no differences in the inflammatory signal IL-1 α , MCP-1, or CXCL5 were detected in the BALF, further supporting the concept that PPAR γ therapeutic effects are not due to simply regulating inflammatory mediator production [ 134 ]. Interestingly, in a mouse model of influenza infection, treatment with 15d-PGJ 2 starting one day after infection dampened inflammatory mediator gene transcription and increased mouse survival and decreased weight loss [ 135 ].…”

Effects of cannabis oil extract on immune response gene expression in human small airway epithelial cells (HSAEpC): implications for chronic obstructive pulmonary disease (COPD)

“…PPAR-gamma is a nuclear hormone receptor with known anti-inflammatory activities (Nencioni et al 2003;Ricote et al 1998). There is a substantial body of literature showing that PPAR-gamma (which was up-regulated by all three cannabis oil extract dilutions) can have beneficial effects in the therapy of COPD, and more specifically, that airway epithelial cells are affected by PPAR-gamma (Belvisi and Mitchell 2009;Morissette et al 2015;Solleti et al 2015). PPAR-gamma was capable of both reducing cigarette smoke-induced inflammation and protecting against Haemophilus influenzae-induced symptom exacerbations in a mouse model of COPD (Morissette et al 2015;Solleti et al 2015).…”

The Lung Immune Response to NontypeableHaemophilus influenzae(Lung Immunity to NTHi)

“…Such immune mediators could potentially have a role in the treatment of NTHi infection/inflammation, although their clinical use would depend upon a significantly improved understanding of the immune response to this bacterium. A recent study described that peroxisome proliferator-activated receptor- γ (PPAR- γ ) activation by rosiglitazone was effective in preventing cigarette smoke-induced neutrophilia exacerbation following NTHi infection [132]. …”