Fisetin and Curcumin beneficial against Pulmonary Fibrosis in mouse model

Pulmonary fibrosis is a disease in which tissue deep in the lungs becomes thick, stiff and scarred over time. The formation of scar tissue is called fibrosis. As the lung tissue thickens, the lungs are not able to properly bring oxygen into the bloodstream. As a result, the brain and other organs don’t get the oxygen they need. In most cases the cause for the disease cannot be found. These cases are called idiopathic pulmonary fibrosis (IPF). Cigarette smoking however is the best recognized and most accepted risk factor for IPF and increases the risk of IPF by about twofold.

IPF is a serious disease that usually affects middle-aged and older adults. IPF has no cure. Many people live only about 3 to 5 years after diagnosis. The most common cause of death related to IPF is respiratory failure. Other causes of death include pulmonary hypertension, heart failure, pulmonary embolism, pneumonia, and lung cancer.

The disease appears to be driven by abnormal and/or dysfunctional alveolar epithelial cells. Alveoli are tiny air sacs in the lungs where gas exchange takes place. Alveolar cells are lining the alveoli of the lungs. The abnormal alveolar epithelial cells (AECs) promote fibroblast recruitment, proliferation, and differentiation, resulting in scarring of the lung, architectural distortion, and irreversible loss of function. Breathlessness and chronic dry cough are the prominent symptoms. At the cellular level, IPF is characterized by alveolar epithelial injury, initiation of inflammatory cascades, exaggerated profibrotic cytokine expression, increased extracellular matrix (ECM) deposition, and the development of fibrotic lesions known as fibroblast “foci”.

Over the past years, polyphenols have been studied for their potential to modulate the production and activity of inflammatory molecules and the researchers in this study selected Fisetin and Curcumin to test their potential therapeutic effects against IPF.

Fisetin is a flavonol, found in many plants fruits and vegetables, such as strawberries, apples, persimmons, onions, and cucumbers. Fisetin inhibits the activity of several proinflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, and nuclear factor kappa B. In addition, fisetin is a potent natural anticancer agent.

The polyphenol curcumin is the active ingredient in the herbal remedy and dietary spice turmeric. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer’s disease, and other chronic illnesses. It has been shown to suppress TNF expression induced by numerous stimuli and by numerous cell types. Recent work has suggested that curcumin acts as a cancer chemopreventive and chemotherapeutic agent. Curcumin inhibits activation of nuclear factor κB and inhibits activation of cyclooxygenase 2 (COX2). It also alters activator protein 1 (AP1) complexes and inhibits Akt.

For the study the researchers used the Bleomycin model which is the most widely used animal model to study human ideopathic pulmonary fibrosis. Balb/C mice were divided in three groups: (a) control (b) bleomycin treated (c) bleomycin + fisetin-treated (d) bleomycin + curcumin-treated and (e) bleomycin + fisetin + mesoporous carbon nanoparticle-treated. In total 19 mice were part of the experiment. Mice in groups (c), (d) and (e) were administered with 40 μl of fisetin, 40 μl of curcumin, and 40 μl of mesoporous carbon nanoparticle (MCN)-conjugated fisetin intratracheally (= via airway catheter inserted in the trachea) at day 7, 14, and 21, and 28 days after which various organs and markers were analyzed.

The study showed that bleomycin is highly effective in causing fibrosis in mice as compared to control groups. The study also demonstrated the antifibrotic action by the flavonoids . The results showed a 19-fold increase in collagen concentration for bleo-treated mice and a significantly lower sixfold increase for bleo + fisetin-treated mice, as well as an even lower threefold increase for bleo + fisetin + MCN-treated mice, and a ninefold increase for bleo + curcumin-treated group. It was also observed that the inflammatory cell count was greatly increased for bleo-treated individuals and decreased by fisetin, the effectiveness of fisetin was increased after addition of MCN. Curcumin also showed anti-inflammatory effects.

In another experiment, bleomycin effectively inhibited the cellular recruitment to the spleen. Treatment with fisetin and curcumin countered this and increased the cellular recruitment in spleen. Colony count was also increased in MCN + fisetin-treated groups. It was also demonstrated that bleomycin effectively decreases the clonogenic potential of the lung cells and that fisetin, MCN-loaded fisetin and curcumin showed regenerative effect in response. In this case curcumin showed the best results. An increased level of cytokines with fisetin treatment, with curcumin treatment and with MCN + fisetin treatment as compared to the bleo-treated sample was measured as well.

As a result of the various specific positive yet not curative effects of the compounds the researchers noted that probably no single agent is going to be sufficient in this disease and that a combination, including agents fisetin and curcumin, will be necessary.

In conclusion, the research suggests that fisetin and curcumin and MCN-loaded fisetin may contribute to a treatment strategy for Idiopathic Pulmonary Fibrosis. Considering that today no cure exists for this disease the results can be considered encouraging. It also again confirms the potential role of dietary use of nutraceuticals in improving and maintaining health.

You can find the study here.

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