Dynamics of Inflammatory and Pathological Changes Induced by Single Exposure of Particulate Matter (PM2.5) in Mice: Potential Implications in COPD.

Chronic Obstructive Pulmonary Disease (COPD) is a progressive disorder of lungs marked by chronic bronchitis and emphysema. Particulate matter (PM2.5), a major component of air pollution has been correlated with COPD incidence. The present work aimed to understand dynamics of cellular/molecular players behind PM2.5-mediated COPD pathogenesis in mice by conducting dose and time-course studies. Single intratracheal exposure of PM2.5 at a dose of either 100 or 200 µg induced inflammatory response in lungs at 4 days. Time course studies showed that inflammation once triggered by PM2.5 is progressive in nature as reflected by data on BALF inflammatory cells at 7/14 days. Similarly, various cytokines/chemokines (KC/IL-6/TNF-α/IL-1ß/G-CSF/MCP-1) peak at either 7 or 14 days. However, inflammation declined sharply at 21 days. Data on LPO/GSH and activities of SOD/Catalase show induction of continuous oxidative stress in lung tissue. Next, enhanced mtROS in the CD11b+ inflammatory cells confirms the redox imbalance in neutrophils/macrophages. A continuous decline in lung function was observed till 28 days. Further, histological analysis of lung tissues at 28 days confirmed the presence of emphysematous lesions, validating the potency of PM2.5 to cause irreversible damage to lungs through complex interplay of various cellular/molecular players which may be exploited as potential preventive/therapeutic targets.

Guggulsterone protects against cigarette smoke-induced COPD linked lung inflammation.

Recently, we have shown that guggulsterone is the principal constituent responsible for protective effects of Commiphora wightii against elastase-induced chronic obstructive pulmonary disease (COPD)-linked inflammation/emphysema. Given that cigarette smoke (CS) exposure is a primary risk factor for COPD and beneficial effects of guggulsterone have not been investigated in CS-induced COPD-linked lung inflammation. The present work was designed to validate the potential of guggulsterone in amelioration of COPD-linked lung inflammation by using a CS-based mouse model of the condition. Male BALB/c mice were exposed to 9 cigarettes/day with 1 h interval for 4 days daily. Guggulsterone was administered daily at a dose of 10 mg/kg orally for 4 consecutive days, 1 h before initiation of CS exposure. Mice were subjected to measurement of lung function followed by procurement of bronchoalveolar lavage fluid (BALF)/lung tissue. BALF was analyzed for inflammatory cells and pro-inflammatory cytokines. Lung tissue was subjected to RT-PCR for gene expression analysis. Data showed that CS exposure resulted in a significant increase in total BALF cells, predominantly neutrophils, and macrophages. Interestingly, guggulsterone administration significantly blunted CS-induced inflammation as reflected by reduced neutrophil and macrophage count. Further, the compound inhibited CS-induced gene expression of pro-inflammatory mediators TNF-α/ IL-1ß/ G-CSF/and KC in lungs along with the production of pro-inflammatory mediators TNF-α/ IL-1ß/ IL-6/ G-CSF/ KC/and MCP-1 in BALF. Further, guggulsterone improved the lung function parameters upon CS exposure. Analysis of mRNA expression of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 suggests that guggulsterone may restore the fine balance between matrix-degrading proteases and its inhibitor in lung tissue upon CS exposure, which may contribute in the development of emphysema at later stages. Overall, our data show that guggulsterone protects against CS-induced COPD-linked lung inflammation by modulating relevant molecular players. Based on the potential effects of guggulsterone in the amelioration of CS-induced lung inflammation, we speculate that guggulsterone might alter chronic CS-induced emphysema.

Immunomodulatory action of synbiotic comprising of newly isolated lactic acid producing bacterial strains against allergic asthma in mice.

Given the reported role of gut-microbiota in asthma pathogenesis, the present work was carried to evaluate immunomodulatory action of newly isolated lactic acid producing bacterial strains Bifidobacterium breve Bif11 and Lactiplantibacillus plantarum LAB31 against asthma using ovalbumin (OVA) based mouse model. Our results show that both strains modulate Th2 immune response potentially through production of short chain fatty acids (SCFAs), resulting in suppression of OVA-induced airway inflammation. Furthermore, synbiotic comprising of both strains and prebiotic, Isomaltooligosaccharide exhibited superior potential in amelioration of OVA-induced airway inflammation through improved modulation of Th2 immune response. Further, synbiotic protects against OVA-induced mucus hyper-production and airway-hyperresponsiveness. Such protection was associated with normalization of gut microbiome and enhanced production of SCFAs in cecum which correlates closely with population of T-regulatory cells in spleen. Overall, our novel synbiotic possesses the ability to fine-tune the immune response for providing protection against allergic asthma.

Protective effect of oleo-gum resin of Commiphora wightii against elastase-induced chronic obstructive pulmonary disease-linked lung inflammation and emphysema: Isolation and identification of key bioactive phytoconstituent.

ETHNOPHARMACOLOGICAL RELEVANCE: Oleo-gum resin of Commiphora wightii (Arnott) Bhandari of family Burseraceae, commonly known as 'guggul', is a well known Ayurvedic drug used traditionally to treat various disorders including respiratory ailments. However, role of C. wightii in chronic obstructive pulmonary disease (COPD) is not known. AIM: The present work was designed to investigate the protective potential of standardized C. wightii extract/and its fractions against elastase-induced COPD-linked lung inflammation and to identify key bioactive constituent(s). MATERIAL AND METHODS: C. wightii oleo-gum resin extract was prepared using Soxhlet extraction technique and the resultant extract was standardized on basis of guggulsterone content using HPLC. The extract was partitioned by different solvents in increasing order of polarity. Standardized extract/its partitioned fractions were orally administered to male BALB/c mice 1 h prior to intra-tracheal instillation of elastase (1U/mouse). Anti-inflammatory effect was evaluated by analyzing inflammatory cells and myeloperoxidase activity in lungs. The various fraction(s) were subjected to column chromatography to isolate bioactive compound. Isolated compound was identified using 1H and 13C-NMR and analyzed for assessment of several inflammatory mediators using techniques like ELISA, PCR, and gelatin zymography. RESULTS: C. wightii extract attenuated elastase-induced lung inflammation in dose-dependent manner and Ethyl acetate fraction (EAF) provided maximum protection. EAF was subjected to column chromatography followed by assessment of bioactivity of each sub-fraction, ultimately leading towards isolation of two compounds i.e. C1 and C2. C1 seems to be the key active principle of C. wightii, as it displayed significant anti-inflammatory activity against elastase induced lung inflammation while C2 largely remains ineffective. C1 was identified as mixture of E- and Z-guggulsterone (GS). Reduction in the elastase induced lung inflammation by GS was associated with downregulation of expression of several COPD linked pro-inflammatory factors such as IL-6/TNF-α/IL-1ß/KC/MIP-2/MCP-1/G-CSF as well as normalization of redox imbalance as indicated by levels of ROS/MDA/protein carbonyl/nitrite/GSH etc. Further, 21 days prolonged administration of GS (10 mg/kg b.wt; once daily) protected against elastase-induced emphysema by mitigating expression/activity of MMP-2/-9 and increasing TIMP-1 expression. CONCLUSION: Overall, guggulsterone seems to be the key bioactive constituent responsible for exerting beneficial effects of C. wightii against COPD.

Isolation & identification of anti-inflammatory constituents of Randia dumetorum lamk. fruit: Potential beneficial effects against acute lung injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Randia dumetorum Lamk. is an Indian traditional medicinal plant that has been used for the treatment of various disorders including respiratory ailments. AIM OF THE STUDY: In continuation of our recent report that the Ethanol soluble fraction (ESF) of Randia dumetorum fruit had potent anti-inflammatory activity against acute lung injury (ALI) in mice, the present work was undertaken to unveil the key bioactive constituents possessing anti-inflammatory action against ALI by employing bioactivity-guided fractionation of ESF. MATERIAL AND METHODS: Different fractions/sub-fractions obtained by column chromatography of ESF were subjected to bioactivity studies by analyzing total and differential count, and protein content in broncho-alveolar lavage fluid (BALF) procured from mice. The most bioactive sub-fraction F3.2 was analyzed for the assessment of various inflammatory mediators using molecular techniques like ELISA, PCR, and western blotting. Further, an attempt was made to separate the key compounds in F3.2 using solvents of differential polarities; and isolated compounds were validated for their anti-inflammatory activity followed by their characterization using spectral techniques like 1HNMR, 13CNMR, FT-IR, and ESIMS Mass Spectrometry. RESULTS: The column chromatography of ESF yielded four fractions (F1, F2, F3, and F4) and data revealed that maximum activity resides in F3. Further fractionation of F3 yielded sub-fractions F3.1, F3.2, F3.3, and F3.4 which when tested for anti-inflammatory potential, showed F3.2 as the most active one. Moreover, the effect of F3.2 on oxidative stress parameters and inflammatory mediators analyzed via biochemical assays, PCR, and ELISA revealed the proficiency of this fraction in amelioration of ALI. F3.2 was then subjected to recrystallization using different solvents and two pure compounds were isolated which were characterized as D-Mannitol and Oleanolic acid (OA). D-Mannitol did not display any bioactivity, but OA showed potent anti-inflammatory activity. CONCLUSION: Considering the ethnopharmacological role of R. dumetorum in respiratory ailments, OA as an aglycone moiety seems to be the main active principle possessing anti-inflammatory potential against ALI.

Particulate matter in COPD pathogenesis: an overview.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder with substantial patient burden and leading cause of death globally. Cigarette smoke remains to be the most recognised causative factor behind COPD pathogenesis. Given the alarming increase in prevalence of COPD amongst non-smokers in recent past, a potential role of air pollution particularly particulate matter (PM) in COPD development has gained much attention of the scientists. Indeed, several epidemiological studies indicate strong correlation between airborne PM and COPD incidence/exacerbations. PM-induced oxidative stress seems to be the major player in orchestrating COPD inflammatory cycle but the exact molecular mechanism(s) behind such a process are still poorly understood. This may be due to the complexity of multiple molecular pathways involved. Oxidative stress-linked mitochondrial dysfunction and autophagy have also gained importance and have been the focus of recent studies regarding COPD pathogenesis. Accordingly, the present review is aimed at understanding the key molecular players behind PM-mediated COPD pathogenesis through analysis of various experimental studies supported by epidemiological data to identify relevant preventive/therapeutic targets in the area.

Implication of mitochondrial ROS-NLRP3 inflammasome axis during two-hit mediated acute lung injury in mice.

Acute lung injury (ALI) caused by acid aspiration often accompanies bacterial components leading to exaggerated inflammation and can result in acute respiratory distress syndrome (ARDS), but the underlying mechanisms behind such an exacerbation remain unclear. NLRP3 inflammasome and mitochondrial ROS (mtROS) have been implicated in ALI but its role in injury caused through two hit i.e. Hydrochloric acid (HCl) + Lipopolysaccharide (LPS) is not known. Therefore, the present study is designed to elucidate the role of mtROS-NLPR3 inflammasome upon "two-hit" mediated ALI. Our data showed that "two-hit" induced ALI results in aggravated lung inflammation as compared to either of single hit(s) as reflected by a steep increase in inflammatory cells particularly neutrophils in bronchoalveolar lavage fluid (BALF). Further, enhanced inflammation was associated with increased mtROS as depicted by data on mean fluorescence intensity (MFI) of MitoSOX+ neutrophils and macrophages in BALF of two-hit simulated mice. Importantly, ALI results in activation of NLRP3 inflammasome as reflected by active caspase-1 protein expression and IL-1ß levels. Interestingly, NLRP3 inflammasome inhibitor, MCC950 suppressed the lung inflammation remarkably. Further, Mito-tempo, a mitochondrial-targeted antioxidant, halted "two-hit" mediated NLRP3 inflammasome activation and IL-1ß release followed by amelioration of lung inflammation. Suppression in MFI of MitoSOX+ stained neutrophils and macrophages by Mito-tempo was associated with down-regulation of phospho-p65-NF-κB and its dependent genes (IL-1ß/TNF-α/IL-6). Overall, our data suggest that NLRP3 inflammasome activation by mtROS plays a critical role in pathogenesis of exaggerated inflammation and therefore targeting mtROS-NLRP3 inflammasome axis may be an attractive option for combating ALI/ARDS.

COVID-19 and ARDS: Update on Preventive and Therapeutic Venues.

A novel coronavirus SARS-CoV-2, which initially originated in China, has outstretched to all nations and turned out to be an intense global concern for both the governments and the public. In addition to the health concerns, the COVID-19 pandemic has caused a tremendous impact on the economic and political conditions of every nation. Ever since the start of the pandemic, the physicians were constrained to rely on the management strategies due to a lack of clear understanding of the disease pathogenesis caused by SARS-CoV-2 infection. Scientists are working tirelessly to gather maximum information about the deadly virus and come up with various strategies, which can be used against COVID-19 infection in terms of therapeutics and vaccine development. It is quite evident that the virus infection leads to acute respiratory distress syndrome (ARDS), and most of the deaths occur due to respiratory failure. As the virus spreads through respiratory droplets, the strenuous exercise of preventive measures and diagnosis at a large scale has been in practice across the globe to prevent transmission. This review amalgamates the various updates and acts as an umbrella to provide insights on SARS-CoV-2 mediated ARDS pathogenesis, the impact of co-morbidities, diagnostics, current progress in vaccine development, and promising therapeutics and immuno-modulatory strategies, highlighting various concerns and gaps that need to be addressed to fight current and future pandemics effectively.

A deleterious interplay between endoplasmic reticulum stress and its functional linkage to mitochondria in nephrolithiasis.

Hyperoxaluria is one of the leading causes of calcium oxalate stone formation in the kidney. Since hyperoxaluria produces Endoplasmic Reticulum (ER) stress in the kidney, it is thus likely that the adaptive unfolded protein response might affect the mitochondrial population as ER and mitochondria share close physical and functional interactions mandatory for several biological processes. Thus this work was designed to study the putative effects of endoplasmic reticulum stress on the renal mitochondria during hyperoxaluria-induced nephrolithiasis. The results showed that hyperoxaluria induced an ER stress led to the unfolded protein response in the renal tissue of experimental rats. Hampered mitochondrion functioning was detected with decreased mitochondrial membrane potential and upsurged mitochondria calcium. These changes in the mitochondria function and ER stress are preceded by apoptosis. The expression of Sigma-1 receptor protein found in the Mitochondria associated ER membranes, the connecting link between ER and mitochondria was found to decrease in the hyperoxaluric rats. Inhibition of ER stress by 4-Phenylbutyric acid prevented the decrease in mitochondria membrane potential and increase in mitochondria calcium observed in hyperoxaluric rats. Also, it restored the protein expression of the sigma-1 receptor protein. On the other hand, N-acetyl cysteine had a nominal impact on the reduction of the ER stress-induced mitochondrial dysfunction. In conclusion, our data showed that hyperoxaluria induces renal ER stress which triggers mitochondria dysfunction, might be via alteration in the sigma-1 receptor protein in the mitochondria-associated ER membranes, which leads to apoptosis, renal injury, and calcium oxalate crystal deposition.

Gallic acid ameliorates COPD-associated exacerbation in mice.

COPD is an inflammatory lung disease, which is often exacerbated with microbial infections resulting in worsening of respiratory symptoms. Gallic acid (GA), a naturally occurring phenolic compound is known to possess anti-oxidant/anti-inflammatory activity. We have recently reported that GA protects against the elastase (ET) induced lung inflammation and emphysema and the present work was designed to investigate the beneficial effects of Gallic acid against ET + Lipopolysachharide (LPS) induced COPD exacerbation like condition in mice model. Our data showed that i.t. administration of LPS at 21 days after ET instillation resulted in significant infiltration of inflammatory cells particularly neutrophils (p < 0.0001) into the lungs along with elevated levels of pro-inflammatory cytokines like TNF-α, IL-1ß and IL-6 (p < 0.0001). Interestingly, daily administration of GA (200 mg/Kg b. wt.) starting 7 days before ET instillation, significantly blunted the ET + LPS induced inflammation as indicated by reduced number of inflammatory cells particularly neutrophils (p < 0.0001) in BALF along with suppression of myeloperoxidase activity (p = 0.0009) and production of pro-inflammatory cytokines (p < 0.0001). Further, GA also restored the redox imbalance in the lungs towards normal. Additionally, phosphorylation of p65-NF-κB was found to be reduced (p = 0.015), which was associated with downregulation in the gene expression of IL-1ß (p = 0.022) and TNF-α (p = 0.04). Conversely, GA treatment resulted in increased protein levels of Nrf2 (p = 0.021) with concomitant increase in transcription of its downstream target genes HO-1 (p = 0.033) and Prdx-1 (p = 0.006). Overall, our data show that GA effectively modulates COPD exacerbation manifestations in mice potentially by restoring redox imbalance in lungs.

COVID-19 Severity: Lung-Heart Interplay.

In December 2019, a novel COVID-19 infection caused by SARS-CoV-2 has emerged as a global emergency. In a few months, the pathogen has infected millions of people in the world. Primarily SARS-CoV-2 infects the pulmonary system which ultimately leads to ARDS and lung failure. The majority of patients develop milder symptoms but the infection turns severe in a huge number of people, which ultimately results in enhanced mortality in COVID-19 patients. Co-morbid conditions, primarily cardiovascular complications and diabetes, have been reported to show a strong correlation with COVID-19 severity. Further, the onset of myocardial injury secondary to pulmonary damage has been observed in critically ill patients who have never reported heart-related ailments before. Due to drastic health risks associated with virus infection, the unprecedented disruption in normal business throughout the world has caused economic misery. Apparently, newer treatments are urgently needed to combat the virus particularly to reduce the severity burden. Therefore, understanding the crosstalk between lung and heart during COVID-19 might give us better clarity for early diagnosis followed by appropriate treatment in patients with the likelihood of developing severe symptoms. Accordingly, the present review highlights the potential mechanisms that may explain the crosstalk between lung and heart so that effective treatment/management strategies can be evolved swiftly in this direction.

Cysteinyl leukotriene D4 (LTD4) promotes airway epithelial cell inflammation and remodelling.

OBJECTIVE: Cysteinyl leukotrienes (CysLTs), a group of inflammatory lipid mediators, are found elevated in obese-asthmatic patients. Leukotriene D4 (LTD4), a representative CysLT, is implicated in promoting lung inflammation and remodelling in allergic asthma, but its role in non-allergic asthma, especially in obese-asthmatic patients, is not known. Here, using primary human small airway epithelial cells (SAECs) we have investigated the mechanism of LTD4-induced inflammation and remodelling and assessed high proneness of obese mice to develop asthma upon challenge with allergen ovalbumin (OVA). METHODS: Primary human small airway epithelial cells (SAECs) were stimulated with different concentrations of LTD4 for different time intervals and various inflammatory markers were measured through cytokine array, membrane-based ELISA and Western blotting. An air-liquid interface (ALI) model of SAECs was used to study the effects of LTD4-induced remodelling in SAECs using Western blotting, H&E staining and PAS staining. Further, OVA-based murine model was used to examine the propensity of high-fat diet (HFD)-fed obese mice to develop asthma symptoms by studying the infiltration of inflammatory cells (assessed by bronchioalveolar lavage (BAL) cytology) and airway remodelling (assessed by histopathology) upon allergen exposure. RESULTS: The human primary small airway epithelial cells (SAECs) treated with LTD4 showed significant alterations in the levels of inflammatory markers such as GM-CSF, TNF-α, IL-1ß, EGF and eotaxin in dose- and time-dependent manner. Further, LTD4 enhanced the activation of inflammasomes as evidenced by increased levels of NALP3, cleaved caspase-1 and IL-1ß. LTD4 also enhanced inflammation by increasing the expression of COX-2 in SAECs. The airway remodelling markers Vimentin and Muc5AC were found elevated in ALI culture of SAECs when stimulated with LTD4, as it also increased TGF-ß levels and activation of Smad2/3 phosphorylation in SAECs. Last, sensitization and challenge of HFD-fed obese mice with OVA showed increased infiltration of inflammatory cells in BAL and enhanced levels of remodeling phenotypes like loss of cilia, mucus cell metaplasia and collagen deposition in mice lung tissues. CONCLUSION: The results suggest that LTD4 could induce inflammatory response in human airway epithelial cell by activating NALP3 inflammasome. LTD4 could further promote airway epithelial cells' remodelling through TGF-ß/smad2/3-mediated pathway. Our in vivo results suggested that obesity predisposed the OVA challenged mice to develop lung inflammation and remodelling akin to asthma-like phenotypes during obesity.

Pharmacological inhibition of poly (ADP-ribose) polymerase by olaparib, prevents acute lung injury associated cognitive deficits potentially through suppression of inflammatory response.

Acute lung injury (ALI) has been reported to be associated with high mortality rate. Moreover, ALI survivors, frequently present chronic cognitive deterioration. We have previously shown that 'two hit' (hydrochloric acid + lipopolysaccharide) induced ALI resulted in cognitive dysfunction through the induction of systemic inflammation. The present study was designed to explore the potential anti-inflammatory effects of olaparib (Poly ADP-ribose polymerase-1 inhibitor), on ALI mediated cognitive impairment. Olaparib was administered at dose of 5 mg/kg body weight (i.p.) 30 min before each hit. Data show that olaparib pre-treatment markedly reduced the neutrophil infiltration, alveolar capillary damage, inflammatory cytokines level (TNF-α/IL-1ß/IL-6) and oxidative stress in the lungs at 24 h after ALI induction. Also, olaparib pre-treatment ameliorated the ALI associated cognitive impairment as assessed by Morris water maze test on weekly basis for 2 consecutive weeks. Further, restoration of cognitive function was associated with normalization of serum levels of TNF-α/IL-1ß and improved the blood brain barrier (BBB) function, as reflected by data on expression of occludin/claudin-5 and extravasation of Evans-blue/FITC dextran in hippocampus at 1 week post injury. Finally, increased mRNA expression of VCAM-1, TNF-α and IL-1ß and NF-κB activation in hippocampus indicate induction of neuro-inflammation, which was downregulated upon olaparib administration. Further, olaparib treatment 1 week after ALI induction blunted the systemic inflammation which was associated with improved BBB and cognitive function. Altogether, our results showed that olaparib protects against ALI and associated cognitive deficits in mice, and thus may offer a new treatment avenue in the area.

Gallic acid protects against the COPD-linked lung inflammation and emphysema in mice.

OBJECTIVE AND DESIGN: Gallic acid (GA) a naturally occurring phenolic compound, known to possess antioxidant/anti-inflammatory activities. The aim of the present work was to investigate the beneficial effects of GA against COPD-linked lung inflammation/emphysema by utilizing elastase (ET) and cigarette smoke (CS)-induced mice model. MATERIALS: Male BALB/c mice were treated with ET (1U/mouse) or exposed to CS (9 cigarettes/day for 4 days). GA administration was started 7 days (daily) prior to ET/CS exposure. Broncho-alveolar lavage was analyzed for inflammatory cells and pro-inflammatory cytokines. Lung homogenate was assessed for MPO activity/GSH/MDA/protein carbonyls. Further, Lung tissue was subjected to semi-quantitative RT-PCR, immunoblotting, and histological analysis. RESULTS: GA suppressed the ET-induced neutrophil infiltration, elevated MPO activity and production of pro-inflammatory cytokines (IL-6/TNF-α/IL-1ß) at 24 h. Reduced inflammation was accompanied with normalization of redox balance as reflected by ROS/GSH/MDA/protein carbonyl levels. Further, GA suppressed phosphorylation of p65NF-κB and IκBα along with down-regulation of IL-1ß/TNF-α/KC/MIP-2/GCSF genes. Furthermore, GA offered protection against ET-induced airspace enlargement and ameliorated MMP-2/MMP-9. Finally, GA suppressed the CS-induced influx of neutrophils and macrophages and blunted gene expression of TNF-α/MIP-2/KC. CONCLUSION: Overall, our data show that GA effectively modulates pulmonary inflammation and emphysema associated with COPD pathogenesis in mice.

Lipid mediators and asthma: Scope of therapeutics.

Lipids and their mediators are known to play a pro-inflammatory role in several human diseases including asthma. The influence of leukotrienes and prostaglandins through arachidonate metabolism in asthma pathophysiology is well established and hence, prompted the way for therapeutic strategies targeting lipid metabolites. In addition, various types of fatty acids have been reported to play a diverse role in asthma. For instance, CD4+ T-lymphocytes differentiation towards T-effector (Teff) or T-regulatory (Tregs) cells seems to be controlled reciprocally by fatty acid metabolic pathways. Further, the dysregulated lipid status in obesity complicates the asthma manifestations suggesting the role of lipid metabolites particularly ω-6 fatty acids in the process. On the other hand, clinical and pre-clinical studies suggests the role of short chain fatty acids in curbing asthma through upregulation of T-regulatory cells or clearance of inflammatory cells through promoting apoptosis. Accordingly, the present review compiles various studies for comprehensive analysis of different types of lipid based metabolites in asthma manifestation. Finally, we have proposed certain strategies which may enhance the usefulness of lipid mediators for balanced immune response during asthma.

Potential of phytochemicals as immune-regulatory compounds in atopic diseases: A review.

Atopic diseases (atopic dermatitis, asthma and allergic rhinitis) affects a huge number of people around the world and their incidence rate is on rise. Atopic dermatitis (AD) is more prevalent in paediatric population which sensitizes an individual to develop allergic rhinitis and asthma later in life. The complex pathogenesis of these allergic diseases though involves numerous cellular signalling pathways but redox imbalance has been reported to be critical for induction/perpetuation of inflammatory process under such conditions. The realm of complementary and alternative medicine has gained greater attention because of the reported anti-oxidant/anti-inflammatory properties. Several case studies of treating atopic diseases with homeopathic remedies have provided positive results. Likewise, pre-clinical studies suggest that various natural compounds suppress allergic response via exhibiting their anti-oxidant potential. Despite the reported beneficial effects of phytochemicals in experimental model system, the clinical success has not been documented so far. It appears that poor absorption and bioavailability of natural compounds may be one of the reasons for realizing their full potential. The current paper throws light on impact of phytochemicals in the redox linked cellular and signalling pathways that may be critical in manifestation of atopic diseases. Further, an effort has been made to identify the gaps in the area so that future strategies could be evolved to exploit the medicinal value of various phytochemicals for an improved efficiency.

Critical role of mitochondrial oxidative stress in acid aspiration induced ALI in mice.

Acute lung injury (ALI) is a pulmonary inflammatory disorder which causes significant mortality in critically ill patients. Intracellular oxidative stress has been considered to be the major component in the pathogenesis of ALI but exact source of intracellular ROS is not clearly known. The present study has been designed to elucidate the role of NADPH oxidase system and/or mitochondrial oxidative stress and its downstream pathway NLRP3 inflammasomes in mouse model of acid aspiration mediated ALI. Our data showed that acid aspiration induced lung inflammation was associated with enhanced oxidative stress as evident by data on MDA levels, nitrite levels and redox imbalance. Further acid aspiration resulted in elevation of expression of NADPH oxidase subunits (gp91 phox/p22 phox/p67 phox) as well as mitochondrial oxidative stress as reflected by aconitase activity, mitochondrial ROS levels. Interestingly, NADPH oxidase inhibitor, apocynin did not alter lung inflammation upon HCl instillation. Conversely, mitochondrial antioxidant mito-tempo resulted in significant amelioration of lung inflammation as indicated by suppression of pulmonary neutrophils and inflammatory cytokines namely IL-1ß, TNF-α, IL-6 in BALF. Analysis of mitochondrial enzymes aconitase/mitochondrial ROS/Mn-SOD confirmed that reduction in lung inflammation by mito-tempo was associated with normalization of oxidative stress in mitochondria. Further, mito-tempo administration blunted phosphorylation of p65- NF-κB at Ser 536. Finally, mito-tempo downregulated HCl-induced NF-κB-dependent pro-inflammatory cytokines (IL-1ß, TNF-α, IL-6) drastically at mRNA levels. Overall, our data support that mitochondrial oxidative stress is crucial in modulating the HCl induced lung inflammation and identifies mitochondrial-targeted antioxidant as a potential therapeutic agent.

Curcumin Ameliorates Ovalbumin-Induced Atopic Dermatitis and Blocks the Progression of Atopic March in Mice.

Curcumin, extracted from the roots of Curcuma longa, has been used as an anti-inflammatory agent since the time of Ayurveda. The present work was designed to evaluate the potential of curcumin in amelioration of ovalbumin (OVA) induced AD in mice. Female BALB/c mice were subjected to skin OVA-patch application for a period of 1 week followed by resting period of 2 weeks, and the same protocol was repeated thrice. Curcumin was administered daily at dose of 20 mg/kg (i.p.) for 7 consecutive days during last sensitization phase. The phytochemical ameliorated the OVA-induced skin pathology as evident by normalization of epidermal thickness and suppressed infiltration of inflammatory cells in dermal region. The expression of Th2 promoting cytokines (TSLP/IL-33) and Th2 cytokines (IL-4/IL-5/IL-13/IL-31) was suppressed markedly along with reduced STAT-6 phosphorylation and GATA-3 expression. Curcumin administration also restored the redox balance and phosphorylation status of P65-NF-κB. Additionally, the epicutaneously sensitized mice challenged with aerosolized OVA developed asthmatic features which were effectively thwarted back upon curcumin treatment as reflected by data on total/differential cells in BALF and mRNA expression of Th2 cytokines in lungs. Overall, our findings demonstrate that curcumin treatment blunts the development of AD as well as associated atopic march in experimental mice.

PARP-1 inhibition provides protection against elastase-induced emphysema by mitigating the expression of matrix metalloproteinases.

In our previous study, we have shown that PARP-1 inhibition (genetic or pharmacological) ameliorates elastase-induced inflammation and emphysema. Since matrix metalloproteinases (MMPs) particularly MMP-2 and MMP-9 are known to play a critical role in emphysema development, the present work was designed to evaluate the effects of PARP-1 inhibition on their expression utilizing elastase-induced mouse model of emphysema. Our data show that olaparib administration at a dose of 5 mg/kg b.wt. (daily) significantly prevented the elastase-induced inflammation as indicated by decreased inflammatory cells particularly macrophages in BALF at 1 week post-injury. In addition, the drug restored the altered redox balance in the lungs of elastase-treated mice toward normal. Further, PCR data show that olaparib administration ameliorates the elastase-induced expression of MMP-2 and MMP-9 without having much effect on the expressions of their inhibitors TIMP-1 and TIMP-2. Next, our data on immunoblot, gelatin zymography, and immunohistochemical analysis indeed confirm that olaparib reduced the elastase-induced expression of MMP-2 and MMP-9. Reduction in the expression of metalloproteinases correlate well with the PARP activity as olaparib treatment suppressed the elastase-induced expression of PAR modified proteins markedly. Overall, our data strongly suggest that PARP-1 inhibition blunts elastase-induced MMP-2 and MMP-9 expression, which may be partly responsible for prevention of emphysema.

PARP inhibition by olaparib alleviates chronic asthma-associated remodeling features via modulating inflammasome signaling in mice.

Despite the reported role of poly(ADP-ribose) polymerase (PARP) in asthma inflammation, its contribution during remodeling is not clearly known. The main aim of the current investigation was to examine the potential of olaparib, a pharmacological inhibitor of PARP against airway remodeling using an ovalbumin (OVA)-based murine model of chronic asthma. The results demonstrated that post-challenge olaparib treatment (5 mg/kg i.p., 30 min after OVA exposure) for six weeks (3 days/week) attenuates inflammation, mucus production, and collagen deposition in lungs. Additionally, olaparib blunted the protein expression of STAT-6 and GATA-3 considerably along with a modest reduction in p65-NF-κB phosphorylation. Furthermore, olaparib normalized the OVA-induced redox imbalance as reflected by data on reactive oxygen species, malondialdehyde, protein carbonyls, and reduced glutathione/oxidized glutathione ratio. Interestingly, the protection offered by olaparib was further linked with the altered level of NLRP3 inflammasome-mediated IL-1ß release and consequent expression of its downstream targets matrix metalloproteinase-9 and transforming growth factor beta. Suppressed collagen deposition in the lungs correlates well with the reduced expression of vimentin upon olaparib treatment. Finally, olaparib restored the expression of histone deacetylase 2, a steroid-responsive element in asthma. Overall, results suggest that olaparib prevents OVA-induced airway inflammation as well as remodeling via modulating inflammasome signaling in mice. © 2019 IUBMB Life, 1-11, 2019.