Amelioration of pulmonary dysfunction and neutrophilic inflammation by PPARγ agonist in LPS-exposed guinea pigs

Abstract

Airway dysfunction and pulmonary neutrophilic inflammation are the major characteristics of inflammatory conditions of lungs like chronic obstructive pulmonary disease (COPD). Lipopolysaccharide (LPS), a constituent of cigarette smoke, has been identified as the most important risk factor for COPD development. Inhalation exposure to LPS or cigarette smoke elicits an inflammatory response accompanied by airway hyperresponsiveness, elevated proinflammatory mediators and inflammatory cells similar to COPD. In the present study, we have evaluated the effects of pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, in LPS-induced pulmonary dysfunction, inflammatory changes and oxidative stress in guinea pigs. Inhalation exposure to nebulised LPS (30 μg ml⁻¹) resulted in significant increase in the breathing frequency and bronchoconstriction accompanied with a significant decrease in tidal volume. Our results demonstrated that the LPS-induced pulmonary dysfunction was temporally associated with neutrophil infiltration as evident from heavy neutrophilia, increased TNFα in bronchoalveolar lavage fluid (BAL), elevated myeloperoxidase (MPO) level and histology of the lung tissue. Exposure to LPS also produced significant increase in tissue malondialdehyde (MDA) level indicating underlying oxidative stress. The results also reveal that pioglitazone (3, 10 and 30 mg kg⁻¹, p.o.) is effective in abrogating the pulmonary dysfunction by attenuating neutrophilia, TNFα release and oxidative stress in LPS-induced model of acute lung inflammation. Results from the present study have added to the emergent body of evidence that PPARγ agonists are effective in the therapy of inflammatory disease of the lungs.

Introduction

Chronic Obstructive Pulmonary Disease (COPD), a major health burden worldwide, is a complex progressive disease characterised by exaggerated airflow obstruction, chronic inflammation and emphysema [1]. Mucociliary dysfunction leading to obstructive nature of the disease is associated with severe pulmonary inflammation marked by neutrophilia along with other inflammatory cells like macrophages and T lymphocytes in airways, lung parenchyma, bronchoalveolar lavage (BAL) fluid and sputum of patients with COPD [2], [3]. Cigarette smoke, which contains bioactive lipopolysaccharide (LPS), is the most common cause of COPD and may also precipitate exacerbations [4]. Inhalation exposure to LPS or cigarette smoke elicits inflammatory response accompanied by airway hyperresponsiveness, elevated proinflammatory mediators and inflammatory cells similar to COPD. The inflammatory cells release various proteolytic and degradative enzymes like neutrophil elastase and matrix metalloproteinases, stimulating hyperplastic goblet cells to degranulate hence causing obstructive bronchiolitis and lung parenchymal destruction (emphysema) [5], [6], [7]. Apart from this, activated epithelial cells and inflammatory cells also release various proinflammatory mediators (TNFα and MCP1), reactive oxygen species and neutrophil chemotactic factors (LTB4 and IL8) which build up the inflammatory cascade and contribute to the complications of debilitating disease [8], [9], [10]. All the above evidences indicate that inflammation contribute heavily in the pathophysiology of COPD and is associated with the release of various proinflammatory mediators from the activated inflammatory cells.

Several lines of evidence implicate the involvement of peroxisome proliferator-activated receptor (PPAR), belonging to the steroid receptor superfamily [11], in various pathological conditions where inflammation predominates [12], [13]. PPAR consists of three isotypes, α, γ, and β/δ, amongst which PPARγ has been shown to be expressed in monocytes/macrophages, lymphocytes, neutrophils and dendritic cells in lungs [14]. PPARγ agonists have been shown to inhibit release of various proinflammatory mediators like TNFα [15], [16]. Accumulating evidences suggest anti-inflammatory effect of PPARγ agonists in airway inflammatory conditions like asthma [17], [18]. Patel and colleagues have also demonstrated that PPARγ agonist exerts its anti-inflammatory effects on human airway smooth muscle (HASM) cells by inhibiting the release of survival factors [19].

Considering the beneficial role of PPARγ agonists in various inflammatory conditions, we have evaluated effects of pioglitazone, a PPARγ agonist, in LPS-induced pulmonary dysfunction, inflammatory changes, TNFα release and oxidative stress.