Category Prednisone And Alcohol

How to Get the Most Benefits from Turmeric Understanding Herbs

How to Get the Most Benefits from Turmeric Understanding Herbs

Like 3 views The Gasoline Antioxidants Marketplace inspects the execution of the Fuel Antioxidants publicize, encasing a best to base judgment of the Fuel Antioxidants showcase condition and the aggressive scene comprehensively. Patients attain this circumstance when the cartilage, which serves as a protective cushioning involving two or much more bones, results in being damaged and the tissues close to the joint turn out to be infected. Healthy patterns, which include compliance with your treatment approach, eating and sleeping well, staying away from stress, common exercise, and maintaining your great weight, will assistance you stay effectively with arthritis. To keep away from these types of conditions and to get a treatment which supplies immediate and long-long lasting aid without triggering any side effects, turmeric and black pepper use herbal solutions to treat joint pain and inflammation. Other fruit juices that are wealthy in antioxidants, vitamins, and anthocyanins (water soluble pigments found in plants which act as antioxidants) include grape juice (purple), pomegranate juice, and cranberry juice. Medications — Nonsteroidal anti-inflammatory drugs, or NSAIDs, (these kinds of as Carprofen, Cure, Etodolac, and Previvor) and glucocorticoids (these as Prednisone) offer you reduction from joint pain and inflammation. These treatments assortment from the pharmaceutical medications, topical lotions, lotions, and gels to the medical and spa treatments like liposuction, thermae, body wraps, aromatherapy, and numerous other people. Your night nightcap as alcohol is broken down inside your body, it produces poisonous by-products that market inflammation, according to the National Institute on Alcoholic beverages Abuse and Alcoholism. Responses to dietary supplements when taken can in reality fluctuate concerning different people today, and consequently the ingestion of any supplement ought to be assessed in training ahead of currently being made use of in competitors. Protects the liver against poisonous substances, prevents gallstones, osteoarthritis, rheumatoid arthritis, diabetes, emmenagogue, jaundice, sleeplessness, may possibly prevent cancer and treat leukemia. Again, we talked about about involving Protection Nutrition and Properly knowledge on a lawsuit to demonstrate the well worth of Protection Nutrition in opposition to the different wrong affirmations from unreliable sources. In case you are enduring joint pains, try adding this to your eating prepare and you will previously start to experience instantaneous ease and comfort thanks to the anti-inflammatory and turmeric with bioperine antioxidant characteristics. These molecules seek out to full this unstable existence by latching on to tissues these types of as blood vessel linings or cell membranes, creating a chronic point out of inflammation within the body. Turmeric and Kidney Disease As an anti-inflammatory, turmeric ginger and black pepper ( simply click the following website page ) may well present some protection towards chronic kidney disease and progression to finish-phase renal failure, according to an article published in Molecules. Curcumin is purported to aid prevent cardiovascular disease and may well be significantly helpful for the prevention of atherosclerosis, a condition characterized by a hardening and narrowing of the arteries. On the other hand, turmeric and black pepper eating a good deal of fresh fruits, vegetables, drinking green teas, employing kitchen area spices in cooking, and taking some antioxidant supplements can replenish the source consistently. Curcumin can essentially increase brain levels of BDNF and by undertaking so, it may perhaps be effective in delaying or even reversing a lot of brain diseases and age-related decreases in brain function. Other exercises that an arthritis client may possibly follow include side bends, arm circles, shoulder shrugs, torso rotations, side lateral raises, wall press-ups, bicep curls, triceps extensions and so on.

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How to Manage Steroid-Induced Osteoporosis

How to Manage Steroid-Induced Osteoporosis

How to Manage Steroid-Induced Osteoporosis . US English Female Endocrinology 5 saat önce 1 Views
Glucocorticoid-induced osteoporosis (GIOP) is a common problem, and the consequences can be catastrophic, especially in an aging population, and in patients with rheumatic disease.
Lenore Buckley, MD, MPH, and Mary Humphrey, MD, PhD, published a nice review of GIOP in the New England Journal of Medicine , highlighting the patients at risk, the consequences, treatments (including calcium, vitamin D, bisphosphonates, anabolic and biologic therapies), guidelines, and recommendations.
Key takeaways from the review include: Risk factors for glucocorticoid-induced fractures include age (age >55), female sex, white race, and long-term use of prednisone at a dose of >7.5 mg per day. Screening for fracture risk should be performed soon after the initiation of glucocorticoid treatment. The risk of fracture among patients who are ages ≥40 can be estimated with the use of bone mineral density (BMD) testing and the fracture risk assessment tool (FRAX). Patients who receive glucocorticoids should be counseled about adequate intake of calcium and vitamin D, weight-bearing exercise, and avoidance of smoking and excessive alcohol intake. Pharmacologic treatment is strongly recommended for anyone who has had a fracture, and for patients who are at least age 40 if, according to FRAX, the risk of major osteoporotic fracture is ≥20%, or the risk of hip fracture is at least 3%. Pharmacologic treatment is also recommended for men who are ages ≥50, and for postmenopausal women, who are on glucocorticoids and have a BMD T score of −2.5 or less (indicating osteoporosis) at either the spine or the femoral neck. Bisphosphonates are recommended as first-line treatment of osteoporosis because of their low cost and safety. The risk of fracture decreases rapidly when glucocorticoids are discontinued. Exposure to glucocorticoids should be minimized as much as possible.
In light of these recommendations, here’s a case study: a woman, age 75, with polymyalgia rheumatica is on prednisone, at a dose of 20 mg daily with a plan to taper the dose to 5 mg daily within 6 months. She is slated to be on drug for 2 years. Her serum 25-hydroxyvitamin D level is 30 ng/ml (74 nmol/L). Her BMD T score is −1.2 at the femoral neck.
How would you advise to prevent GIOP and fracture in this patient?
Jack Cush, MD , is the director of clinical rheumatology at the Baylor Research Institute and a professor of medicine and rheumatology at Baylor University Medical Center in Dallas. He is the executive editor of RheumNow.com . A version of this article first appeared on RheumNow, a news, information and commentary site dedicated to the field of rheumatology. Register to receive their free rheumatology newsletter.
2019-01-12T10:00:00-0500

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Osteoporosis. Not just a women’s disease! – Share As we a

Osteoporosis. Not just a women’s disease! – Share As we a

Share As we age we know our body follows suit, and a big part of that process happens to be in our bones. They lose mass over time, becoming more fragile and weak. Although this is symptomatic of growing older, there are a number of Canadians who suffer from a larger risk of bone loss due to osteoporosis.
by Lara Ceroni
“UNDERSTANDING OSTEOPOROSIS TODAY IS THE FIRST STEP IN HELPING PREVENT FUTURE BONE LOSS AND SEPARATING FACT FROM FICTION.”
A debilitating (and oftentimes undetected) condition, osteoporosis happens when bones become porous, meaning overall density is greatly reduced. Progressively, bones become more brittle, which can lead to a higher risk of fracture. As many as two million people in Canada suffer from this degenerative disease, but when it comes to understanding the facts of osteoporosis, many feel left in the dark. Being able to differentiate between truth and fiction can be challenging, mostly because so many sources exist, some of which aren’t based on actual fact.
Understanding osteoporosis today is the first step in helping prevent future bone loss and separating fact from fiction can help with proper treatment should you or a loved one receive the diagnosis. Dr. Famida Jiwa, president and CEO, Osteoporosis Canada, helps dispel some of the more common myths about bone health.
Myth: Osteoporosis is a woman’s disease
Yes, there is prevalence towards women and osteoporosis because, as women age, their hormonal balance changes: Estrogen levels drop and that will dictate more bone loss. But, as Dr. Jiwa stipulates, this by no means suggests it’s only women who deal with osteoporosis. In fact, one area where diagnosed men outrank women, is in fatality rates after breaking a hip: Statistics show 37 percent of men die in the first year following this kind of mishap.
Myth: I exercise regularly and also eat well, so I can’t be at risk.
Exercise is good for overall body health, but when it comes to building bone strength, weight-bearing exercises are best. Those may include: weight training, walking, hiking, jogging, climbing stairs, tennis and dancing. Swimming and cycle are not weighBone requires that “gravitational push within the bones to create more density,” says Dr. Jiwa.
Doctors may suggest that patients take vitamin D or calcium supplements to improve bone health. Photo: Flickr/Creative Commons, Bradley Stemke. Eating well is also part of the equation, but a good diet for bone strength is one that is rich in vitamin D and calcium. According to Dr. Jiwa, no matter how much you eat your greens and veggies, getting the recommended dosage of vitamin D and calcium to stave off osteoporosis is a challenge not often met. Supplements are likely needed. Consult with your physician or pharmacist about recommended dosage.
Beyond diet and exercise, there are other factors that could increase your risk for osteoporosis:
Family history: Having a parent who had osteoporosis or broken a hip, puts you at higher risk. Alcohol consumption: Too much can diminish your bone strength. Glucocorticoid therapy: If you’re currently using glucocorticoid therapy (i.e. prednisone) to treat such conditions as rheumatoid arthritis, Crohn’s disease, colitis and obstructive pulmonary disease, your bone health may be compromised. Myth: I’ve got osteoporosis and there’s nothing I can do about it.
Fortunately, this is a false claim, says Dr. Jiwa. It’s never too late to take steps to stop further bone loss. For one, increasing your calcium and vitamin D intake works, while also committing to a regime of weight training and therapeutic options, which could include medications prescribed by a doctor.
They might include a drugs that fall under the bisphosphonates category. These medications put the brakes on further breakdown of bone. Newer drug therapies can actually help rebuild bone and hormones may be prescribed to prevent bone deterioration.
Myth: Osteoporosis only affects older people.
Both men and women reach peak bone mass in their early 20s, but once we hit our mid-30s it starts to fall naturally. For Dr. Jiwa, educating yourself on the importance of bone health should start much earlier life instead of waiting until our 60s, or worse yet, we fracture a bone.
A family history of hip fractures is a risk factor for compromised bone health. Photo: Flickr/Creative Commons, My Arthritis. “People look at osteoporosis as a diffused disease without really understanding what it is,” she says. “If we can educate people on the risks, they will likely work to improve their bone health in those earlier years.”
She gives the example of falling on ice. If you fall, the blame automatically goes to the ice, not the bone. For Dr. Jiwa, we need do a better job of connecting the dots. If I fall, my body should have the integrity to hold without breaking a bone. If it doesn’t, then it’s something that needs to be investigated further.
This article appeared originally on YouAreUNLTD.com
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A 77-year-old woman from Plainview, N.Y., wrote that after a recent bone density test, she was told she had osteopenia. Although she is very active, takes 1,500 milligrams of calcium and 400 international units of vitamin D every day and uses a…

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Dog Ear Infection Symptoms and Treatment

<h1>Dog Ear Infection Symptoms and Treatment</h1>

Dog Ear Infection Symptoms and Treatment

Guide To Dog Ear Infection Causes, Symptoms, and Treatment Table of Contents Overview | Symptoms | Diagnosis | Treatment | Q&A | Brochures Summary:
“Dog ear infections can be infuriatingly difficult to treat and account for 20% of visits to the veterinarian. They are more easily treated if caught early as an otitis externa or outer ear problem.
Look for telltale signs such as dogs that scratch or paw at the ears and head shaking. Skin irritation and itch may or may not be present. Other signs include ears that cause pain to the dog when touched or inflammation inside the ear. Dogs that continually scratch the ear can cause a more serious problem which results in the rupturing of the tympanic membrane.
Common causes of dog ear infection are water trapped in the ear, foreign material (grass awns), yeast, atopy (inhaled seasonal allergy), hypersensitivity to foods, bacteria, immune mediated or autoimmune diseases (pemphigus foliaceus) or mites (Otodectes and Demodex). Ear infections are not caught from another pet.
Treatment depends on the underlying condition and should be in consultation with a veterinarian. If caught early, ear infections in dogs can be easily treated. Treatment options range from prescription antibiotics or anti-fungal agents, ear cleansers and natural ear drops. Veterinarians often add a glucocorticoid such as prednisone, which can help reduce inflammation and improve the speed of healing. Do not apply any cleanser or treatment before speaking to a veterinarian and avoid alcohol based products, as these can be irritating.”
For prevention, all dogs should have canine ear hair plucked on a regular basis, particularly those breeds that are susceptible to a dog ear infection.” Cocker Spaniel with Otitis (Ear Infection) Photo Credit: Washington State University School of Veterinary Medicine Overview
Ear infections are one of the most common and frustrating problems dealt with by dog owners and veterinarians. Ear infections are usually very treatable if caught and addressed early, so it is beneficial for dog owners to be aware of the common signs of ear infections, as well as treatment and prevention.
A dog ear infection, otherwise known as otitis externa (inflammation of the ear canal), or just otitis, occurs when a pathogen invades the tissue of the external ear canal and causes an infection. The pathogen involved can be either yeast or a bacterial organism. Otitis occurs in any breed of dog during any season, but is more common in the spring and summer months. Otitis is often associated with allergic conditions, such as atopy and food allergy. Sometimes the otitis will be accompanied by itchy or irritated skin, but many times it is not. In fact, in many cases of food allergy chronic otitis is the only abnormal sign the dog displays. Anatomy Model of Dog Ear Anatomy. Only A Veterinarian Should Use A Cotton Tipped Applicator. For Safety, Hold The Applicator So That Only An Inch of It Can Be Inserted.
Dog ears are structured differently than human ears making them more susceptible to ear infection. In humans the ear canal travels horizontally whereas in a dog the canal moves from the outer ear vertically downward before make a turn toward the ear drum. This turn makes it easier to collect debris, dirt and wax, allowing bacteria to colonize and take hold as an infection. Types of Ear Infections
There are three main types of ear infections and each requires different type of treatment. Dog Ear Mites Ear mites (Otodectes cynotis): This is the most common type of ear infection. Usually both ears are affected. To treat it, the ears are first cleaned thoroughly. Then a medication such as ivermectin is massaged into the ear. A second treatment may be performed in two to four weeks, just to make sure all the mites have been killed.It is generally recommended that all pets in the home be treated at the same time. You may also want to clean the rooms where you dog lives to make sure that no mites remain and then cause reinfection. A good choice for indoor mite removal is Benzarid. They also sell a power steam cleaner for effective outdoor mite removal. Secondary infections in dogs with ear mites are common and generally involve bacteria or yeasts. Bacterial or fungal/yeast ear infections : These are usually simple, first time dog ear infections. In this case the ear tissue is normal except for being a little irritated. One or both ears may be affected. These respond readily to treatments for dog ear infections. The affected ear is cleaned daily. The cleanser may contain a topical steroid to reduce inflammation and/or an antibiotic to fight infection. Oral antibiotics may also be given, particularly if your dog has a fever, which would indicate a bacterial infection. Avoid alcohol based products. See your veterinarian at the first sign of an ear infection since early detection results in a faster and better result. Swimming Chronic, repeat ear infections
The ear tissue becomes thicker, spongier, and more productive (produces more wax and other discharge). These infections improve with treatment but keep coming back. Both ears are usually affected. These are most common in dogs with pendulous ears like cocker spaniels and basset hounds.
When there are repeat dog ear infections, it’s often due to allergies. There are mast cells concentrated in the dog’s ear canals, just like the mast cells in humans’ respiratory tracts. These mast cells produce histamines and other inflammatory chemicals in response to allergens. When these chemicals are released in the ears, they stimulate the production of excess ear wax and other secretions.
The waxy, gooey ears provide an ideal place for skin bacteria to grow. They also attract yeast spores. To treat these infections, it is necessary to deal with the underlying allergies, the bacterial infection, and the yeast infection. Predisposing and Perpetuating Factors
Certain breeds are predisposed to developing dog ear infections, but any breed can be affected due to these related problems. Eliminating these factors do not mean that a dog will never have another ear problem . Breeds with Excessive Hair that has been plucked (iatrogenic trauma): Poodles English sheepdog, Airedale terrier Anatomical Factors such as breeds with pendulous ears: Cocker spaniel, Labrador Retriever Narrow ear canals or folded ears: Shar-pei Moisture in the ears from swimming or high humidity environment Under treatment due to a lower dose of medications than is needed when treated or the length of treatment is too short Presence of bacteria or Malassezia pachydermatis (yeast) Infection that progresses to the middle ear (Otitis media) Otitis Externa (Dog Ear Infection) In a Chocolate Labrador Dogs with pendulous ears are more susceptible to Ear Infection.Scratching and head tilting are two of the symptoms. Photo Credit: Washington State University, School of Veterinary Medicine Symptoms
It is usually fairly easy to tell when a pet is experiencing the onset of an external dog ear infection. The classic signs of otitis are head-shaking, face rubbing on furniture, shaking or tilting the head, pawing or scratching at the ears, and reddened/inflamed ears with discharge or abnormal debris present in the canal. Dogs with chronic or more advanced cases may be lethargic and avoid play in addition to acting as in pain when the ears are touched. If an ear infection spreads to the middle ear, a dog can have vertigo like symptoms and appear dizzy or off-balance. Dog Ear Infection in 3 year old Cocker Spaniel. Ear wax exudate is present, swollen and ear canal inflamed Source: Joel Mills
In more severe cases of otitis, a very pungent odor may also be present and the dog’s ears may be very painful to the point where it will not allow or will cry out with handling of the head or ears. Inhalant Allergy: Redness on ears and ear canal (may be only symptom) Contact Allergy: Suspect problems with topical medications if dog ear infection gets worse after treatment
In order to prevent a dog ear infection from becoming severe, it is important for owners to recognize and act on the signs of early ear infections. If a dog is shaking his head or scratching his ears more than normal, this should not be ignored. Lift the dog’s ear pinna and look into the ear canal. If you see reddened or inflamed ear tissue or abnormal discharge within the ear canal, you should seek veterinary care right away.
It is best to avoid over-the-counter ear cleaners and medications until after you have spoken to the veterinarian. Many of these cleaners contain alcohol, which can be irritating and painful to an already irritated ear. Furthermore, putting agents into the ear before the veterinary examination can hinder the vet’s ability to properly diagnose the type of infection. Ear Discharge and Causes of Ear Infection in Dogs
The color and consistency of any dog ear discharge can indicate the cause of a canine ear infection. Vets will commonly test the discharge in order to reach a diagnosis. Exudates/Discharge, Symptoms and Related Causes of Ear Infection in Dogs
Dog Ear Infection Symptoms
Probable Cause of Dog Ear Infection Dark Brown to Black and Waxy

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Fit by 40 recap: week 1

<h1>Fit by 40 recap: week 1</h1>

Fit by 40 recap: week 1

14 miles of walking/jogging.
Not too shabby.
My diet has been on point all week. I’ve had Shakeology every morning. Oh and I’ve been on top of my meds, including my vitamins. Weigh in is on Wednesday.
I haven’t had any alcohol so far, but that’s likely to change tonight, because it’s date night. It’s all good though. Gotta find the balance.
As of Thursday, I’ll be done with my prednisone, and I’m scared about how my body will react. The plan is, however, to keep calories low during flares, and just go balls to the wall on activity whenever my body allows for it. Share this:

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Yangyin Yiqi Mixture Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats through Inhibiting TGF-1/Smad Pathway and Epithelial to Mesenchymal Transition

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Yangyin Yiqi Mixture Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats through Inhibiting TGF-1/Smad Pathway and Epithelial to Mesenchymal Transition

Yangyin Yiqi Mixture Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats through Inhibiting TGF-1/Smad Pathway and Epithelial to Mesenchymal Transition Lihong Meng , 1 Xiaomei Zhang , 2 Hong Wang , 3,4 Huan Dong , 1 Xiaofeng Gu , 1 Xiaolin Yu , 1 and Yushan Liu 1
1 Beijing University of Chinese Medicine, No. 11 on North 3rd Ring Road, Beijing 100029, China 2 Department of Respiratory Medicine, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, No. 6 on 1st District of Fangxingyuan, Beijing 100078, China 3 Beijing Chinese Medicine Hospital, Shunyi Hospital, No. 5, Zhanqian East Street, Shunyi District, Beijing 101300, China 4 Beijing Chinese Medicine Hospital Affiliated to Capital Medical University, No. 23, Houjie Street, Art Museum, Dongcheng District, Beijing 100010, China
Correspondence should be addressed to Xiaomei Zhang ; and Hong Wang ;
Received 27 August 2018; Revised 6 December 2018; Accepted 16 December 2018; Published 3 January 2019
Academic Editor: Yuewen Gong
Copyright © 2019 Lihong Meng et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
Objective . The aim of the current study was to investigate the protective effect of Yangyin Yiqi Mixture (YYYQ) on Bleomycin-induced pulmonary fibrosis in rats based on TGF- β 1/Smad signal pathway and epithelial to mesenchymal transition (EMT). Methods . 120 Wistar rats were randomly divided into six groups: control group, BLM group, BLM + Pred group, BLM+YYYQ-L group, BLM+YYYQ-M group, and BLM+YYYQ-H group. Rats were given an intratracheal instillation of 3 mg/kg BLM to establish the pulmonary fibrosis model and followed by different dosages of YYYQ (11, 22, 44g/kg, via intragastric gavage) or prednisone soluble (4.2mg/kg, via intragastric gavage) or water. After 14 days and 28 days, tissue sections were stained with hematoxylin-eosin and Masson’s trichrome to observe histopathological changes. Protein levels of TGF- β 1, CTGF, Interleukin 18, and hydroxyproline were detected by ELISA method, and mRNA expressions of TGF- β 1, T β RI, T β RII, Smad3, Smad7, α -SMA, E-cadherin, laminin, and collagen I were detected by RT-PCR. Results . TGF- β 1, CTGF, Interleukin 18, and hydroxyproline levels and mRNA expression of TGF- β 1, T β RI, T β RII, Smad3, α -SMA, laminin, and collagen I were significantly increased ( p <0.01), while Smad7 and E-cadherin levels were significantly decreased in BLM group ( p <0.01). YYYQ-M and YYYQ-H group had downregulated the TGF- β 1, CTGF, hydroxyproline contents, and mRNA expression of TGF- β 1, T β RI, T β RII, Smad3, α -SMA, laminin, and collagen I and upregulated mRNA levels of Smad7 and E-cadherin significantly ( p <0.01 or p <0.05). The result from the present study, which was also supported by histological evidence, suggested that YYYQ-M group and YYYQ-H group exhibited better treatment effect on Bleomycin-induced pulmonary fibrotic rats when compared to that of BLM + Pred group ( p <0.01). Meanwhile, the effect of YYYQ, in three different dosages, on the level of interleukin 18 was not significant. Conclusion . These results showed that YYYQ has the potential of ameliorating the progression of pulmonary fibrosis, and the mechanism may be related to suppressing TGF- β 1/Smad signal pathway and EMT in BLM-induced pulmonary fibrosis of rats. 1. Introduction
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease, which is characterized by chronic inflammatory response, excessive proliferation of fibroblasts, aberrant deposition of extracellular matrix (EMC), and abnormal repair and remodeling of lung tissue [ 1 ]. Studies showed that many causes, such as environmental pollution, bacterial infections, smoking, and gastroesophageal reflux, are closely related to the onset of IPF [ 2 – 5 ]. Since IPF can deteriorate lung functions, which may then lead to respiratory failure and eventually death, the prognosis of IPF is usually poor. Although studies had reported that combination of glucocorticosteroids (such as prednisone), azathioprine, and N-acetylcysteine was unable to decrease the mortality and morbidity rate of IPF, such combination remained as the conventional treatment for IPF patients in order to relieve inflammation, suppress immune responses, and relieve signs and symptoms during the course of the disease [ 6 ]. Pirfenidone and nintedanib are the two newly developed antipulmonary fibrotic drugs which can significantly improve lung function and delay the progression of IPF. However, the usage of such drugs is often limited in clinical settings due to its high price and side effects [ 7 , 8 ]. Hence, it is necessary that further research is to be carried out to explore new treatment methods for IPF.
Transforming growth factor- β 1 (TGF- β 1) is a well-recognized profibrotic factor, which plays a crucial role in resulting multiple organs fibrosis through increasing the production of glucose and proteoglycans, promoting the transport of amino acids, and promoting the deposition of extracellular matrix [ 9 ], among which, Smad-mediated TGF- β 1 is regarded as one of the most important signaling pathway in causing fibrosis. Meanwhile collagen (type I and type II), fibronectin, hydroxyproline, and laminin are the few main components of extracellular matrix [ 10 , 11 ]. Lucarini L. et al. [ 12 ] found that inhibition of TGF- β /Smad pathway could significantly improve the static compliance of airway and lung, reduce lung tissue hardness, and downregulate the expression levels of inflammatory factors such as tumor necrosis factor- α , interleukin 1 β , iNOS, and COX-2, reduce α -SMA expression in BLM-induced pulmonary fibrosis in mice, and ameliorate the progression of signs and symptoms of pulmonary fibrosis.
Fibroblasts and myofibroblasts, which can be resulted via activation of original fibroblasts, proliferation, and differentiation of bone marrow-derived stem cells or epithelial-mesenchymal transition (EMT), are the main effector cells that produce extracellular matrix in pulmonary fibrosis [ 13 ]. This is in agreement with Tanjore et al. [ 14 ], in which the team reported that about one-third of fibroblasts in lung tissues of BLM-induced pulmonary fibrotic mice was derived from type II lung epithelial cells through the process of EMT. EMT is characterized by low expression of epithelial cell markers such as E-cadherin and ZO-1 and overexpression of mesenchymal markers such as α -Smooth muscle actin ( α -SMA) and vimentin [ 15 , 16 ]. Meanwhile, TGF- β 1 is regarded as an important triggering factor for the onset of pulmonary fibrosis by accelerating the process of transformation of alveolar epithelial cells into mesenchymal myofibroblasts [ 17 , 18 ]. The study conducted by Ji Y. et al. further supported this statement as a result of their study proved that TGF- β 1 stimulated the morphogenesis of A549 cells and induced EMT [ 19 ]. In a nutshell, the levels of SMA, vimentin, and types I and III collagen can be decreased by inhibiting the TGF- β 1/Smad pathway. On the other hand, E-cadherin expression can be further enhanced by inhibiting TGF- β 1/Smad pathway.
From the perspective of traditional Chinese medicine, deficiency of qi and yin, and stasis of blood and phlegm formed the main pathogenesis of IPF [ 20 ]. YYYQ is an effective prescription created by Wen Zhenying, a national famous doctor of Chinese medicine. The main function of YYYQ is to replenish qi and nourish yin and promote blood circulation and detoxification, and the curative effect of YYYQ against IPF has been proven in both clinical and experimental studies [ 21 , 22 ]. The aim of our study was to explore the protective effect of YYYQ on BLM-induced pulmonary fibrosis in rats based on TGF- β 1/Smad signal pathway and EMT. 2. Materials and Methods 2.1. Animals
120 adult SPF Wistar rats (male, 6 weeks old, weighting around 200g) were purchased from Vital River Laboratory Animal Technology Co., Ltd., Beijing, China, and housed in laboratory animal center of Dongfang Hospital, Beijing University of Chinese Medicine. All rats were kept at a constant temperature of 25°C and humidity of 45%-55% with a 12-hour light-dark cycle and free access to diet and tap water. The experiment protocol was approved by the Ethical Committee for the Experimental Animals at Dongfang Hospital, Beijing University of Chinese Medicine. 2.2. Chemicals and Reagents
YYYQ consists of astragalus mongholicus (huangqi, 15g), Codonopsis pilosula (dangshen, 15g), radix scrophulariae (xuanshen, 15g), radix glehniae (beishashen, 15g), rhizome polygonati (huangjing, 10g), radix lithospermi (zicao, 10g), ligusticum wallichii (chuanxiong, 10g), smoked plum (wumei, 10g), radices trichosanthis (tianhuafeng, 10g), and pericarpium citri reticulatae (chenpi, 10g). All the herbs are measured up to the criteria of the Pharmacopoeia of the People’s Republic of China (2015 Edition). The decoction was made by Preparation Center of Dongfang Hospital from crude herbs. All the herbs were soaked in water for 1 hour and the mixture was boiled for half an hour for extracted solution for the first time. Then, the herbs were decocted for 20 minutes again after immersing for 30 minutes. The decoction of this was mixed twice together and then further concentrated to 2 g/ml.
Bleomycin (BLM) was provided from Haisun Pfizer pharmaceuticals Co. Ltd., Zhejiang, China. Prednisone was obtained from Lisheng Pharmaceutical Co., Ltd., Tianjin, China. TRIzol reagent was purchased from Tian Gen biotechx Co., Ltd., Beijing, China. PrimeScript RT reagent kit with gDNA Eraser was purchased from Takara Biotechnology, Co., Ltd., Beijing, China. TGF- β 1 kit was purchased from R&D Systems, Inc. Connective tissue growth factor (CTGF) and interleukin 18 kits were purchased from Abbexa. Hydroxyproline kit was obtained from Cell Biolabs. 2.3. Experiment Protocol and Model Establishment
Rats were anesthetized with abdominal injection of 1% pentobarbital sodium (45mg/kg) and given an intratracheal instillation of 3 mg/kg BLM, followed by immediate turning of the rats to ensure thorough drug distribution in the lungs. The rats were randomly divided into six different groups (n=20 per group), namely, BLM group, BLM+ Pred group, BLM+ YYYQ-L group, BLM+ YYYQ-M group, and BLM+ YYYQ-H group. The dosage of medication given to the rats was calculated according to the conversion of animal dose to human equivalent doses based on body surface area [ 23 ]. Rats in six different groups were intervened as follows: (1) control group and (2) BLM group: given the same volume of normal saline; (3) BLM+ Pred group: gavage with prednisone suspension 4.2mg/kg every day; (4) BLM+ YYYQ-L group (5) BLM+ YYYQ-M group and (6) BLM+ YYYQ-H group: gavage with YYYQ mixture at doses of 11 g/kg, 22 g/kg, and 44g/kg every day. On day 14 and day 28 after initial instillation, eight rats from each group were dissected randomly, with their lungs removed. The left lungs were fixed with 4% paraformaldehyde for histopathological examination. Meanwhile, the right lungs were stored in -80°C for RT-PCR assay and the sera were collected and stored in -20°C for ELISA assay. 2.4. Lung Histopathology Examination
The paraffin-embedded pulmonary specimens were sectioned into 4 μ m thick slices and then deparaffinized in xylene for 15 min, hydrated in gradient alcohol, and then rinsed with 1% phosphate-buffered saline three times. Then these slices were stained with hematoxylin and eosin (H&E) and Masson’s trichrome for morphologic detection. The H&E staining was used to assess the alveolitis inflammation and Masson’s staining was used to observed degree of lung fibrosis. Alveolitis and pulmonary interstitial fibrosis were quantified by Szapiel scoring system [ 24 ]. 2.5. Enzyme-Linked Immunosorbent Assay (ELISA)
TGF- β 1, CTGF, interleukin 18, and hydroxyproline kits were used to detect the protein expression of TGF- β 1, CTGF, interleukin 18, and hydroxyproline in sera of rats according to the manufacturer’s protocols. 2.6. Real-Time Polymerase Chain Reaction (RT-PCR)
Total RNA in the lung was extracted using the TRIzol reagent and reverse transcribed to cDNA using the Prime Scriptr RT reagent kit according to the manufacturer’s instructions. RT-PCR was performed on the cDNA samples using the SYBRr Premix Ex TapTM II. The reaction conditions were as follows: 95°C for 30 s, followed by 40 cycles of denaturation at 95°C for 5 s and extension at 60°C for 34 s. All amplifications were done in triplicate and repeated three times. The data were analyzed by the QuantStudio 7 Flex detection system. Cycle threshold (CT) values were analyzed by the comparative CT (ΔΔCT) method, and the relative amount of target mRNA ( ) was obtained by normalizing to endogenous glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Information of RT-PCR primers is shown in Table 1 . Table 1: Primer information for real-time polymerase chain reaction. 2.7. Statistical Analysis
All the data in the study were expressed as mean ± standard deviation (SD) and analyzed with SPSS 20.0. One-way analysis of variance (ANOVA) and least significant difference (LSD) test were used to analyze the data with normal distribution, and Tamhane’s T2 test was used to evaluate the nonnormally distributed continuous data. Value p < 0.05 was considered as a significant difference in statistics. 3. Results 3.1. YYYQ Attenuated BLM-Induced Pulmonary Fibrosis in Rats
H&E staining was used to observe the changes of alveolar inflammation in lung tissues. The results are shown in Figure 1 . Under the microscope, samples in control group indicated that the alveolar wall was intact, the alveolar cavity was clear, no bleeding or exudate was found in the alveolar and bronchial cavity, and no obvious inflammatory cells infiltration was observed on day 14 and day 28. On day 14, samples from BLM group showed that alveolar cavity and part of bronchi structure had collapsed and destructed, alveolar septal became thick and swollen, and large amount of inflammatory cells infiltration was observed in pulmonary interstitial tissues and alveolar tissues. On day 28, pulmonary interstitial inflammation was reduced, while the alveolar structure was replaced by collagen fibers because of the fibroblast proliferation. In summary, the histopathological results showed that lesions of lung tissues from the rats in BLM group and all the treatment groups were more severe compared to that of rats in control group. However, thickness of alveolar septa and infiltration of inflammatory cells among the rats in BLM + Pred group and different dosages of YYYQ groups was significantly reduced when compared to that of rats in BLM group. Figure 1: H&E staining of lung tissues (100x). (a) Control group treated by normal saline on days 14. (b) Control group treated by normal saline on days 28. (c) BLM group induced pulmonary fibrosis and treated by normal saline on days 14. (d) BLM group induced into pulmonary fibrosis and treated by normal saline on days 28. (e) BLM + Pred group treated by prednisone on days 14. (f) BLM + Pred group treated by prednisone on days 28. (g) BLM + YYYQ-L group treated by low dose of YYYQ on days 14. (h) BLM + YYYQ-L group treated by low dose of YYYQ on days 28. (i) BLM + YYYQ-M group treated by middle dose of YYYQ on days 14. (j) BLM + YYYQ-M group treated by middle dose of YYYQ on days 28. (k) BLM + YYYQ-H group treated by high dose of YYYQ on days 14. (l) BLM + YYYQ-H group treated by high dose of YYYQ on days 28.
H&E score is shown in Table 2 and Figure 2 . On days 14 and 28, the alveolitis scores in all groups treated with BLM were higher than that in control group ( p <0.01), whereas compared with BLM group, BLM+YYYQ-M group and BLM+YYYQ-H group have lower alveolitis scores ( p <0.01). However, BLM + Pred group did not show an advantage in improving pulmonary fibrosis alveolitis than YYYQ groups. Table 2: Histopathologic data of each group on 14d and 28d were presented as mean± SD (n=8). Compared with control group ( p <0.05, p <0.01), compared with BLM group ( p <0.05, p <0.01), compared with BLM + Pred group ( p <0.05, p <0.01), and compared with BLM + YYYQ-L group ( p <0.05, p <0.01). Figure 2: Scores of alveolitis.
Masson’s trichrome staining was used to observe the degree of pulmonary fibrosis, in which the microscopic images are illustrated in Figure 3 . Control group showed that normal lung tissue structure and slight collagen deposition in the alveolar septa. On the other hand, BLM group indicated severe collagen deposition, obliteration of interalveolar septum, and damage of lung structure, whereby the alveolar space was replaced by collagen fibrosis and normal alveoli was further deteriorated on day 28. The results also indicated that the level of destruction of pulmonary interstitium and severity of collagen fibrosis in the alveolar septa were reduced in BLM + Pred group and different dosage of YYYQ groups. Figure 3: Masson’s staining of lung tissues (200x). (a) Control group treated by normal saline on days 14. (b) Control group treated by normal saline on days 28. (c) BLM group induced pulmonary fibrosis and treated by normal saline on days 14. (d) BLM group induced into pulmonary fibrosis and treated by normal saline on days 28. (e) BLM + Pred group treated by prednisone on days 14. (f) BLM + Pred group treated by prednisone on days 28. (g) BLM + YYYQ-L group treated by low dose of YYYQ on days 14. (h) BLM + YYYQ-L group treated by low dose of YYYQ on days 28. (i) BLM + YYYQ-M group treated by middle dose of YYYQ on days 14. (j) BLM + YYYQ-M group treated by middle dose of YYYQ on days 28. (k) BLM + YYYQ-H group treated by high dose of YYYQ on days 14. (l) BLM + YYYQ-H group treated by high dose of YYYQ on days 28.
Masson’s score is shown in Table 2 and Figure 4 . The scores of pulmonary fibrosis in all groups treated with BLM were higher than control group on days 14 and 28 ( p <0.01), and the event of interstitial fibrosis was more severe on day 28, indicating that pulmonary fibrosis was mainly observed on day 28. On day 14, BLM+YYYQ-H group significantly inhibited the progression of pulmonary fibrosis ( p <0.01). On day 28, the fibrosis scores for all treatment groups were significantly lower than BLM group ( p <0.01). Meanwhile, BLM+YYYQ-H group showed better treatment effect than BLM + Pred group ( p < 0.05). Figure 4: Scores of pulmonary fibrosis. 3.2. YYYQ Decreased the Protein Expression of TGF- β 1, CTGF, Interleukin 18, and Hydroxyproline in Sera
ELISA was used to detect the levels of protein concentration of TGF- β 1, CTGF, interleukin 18, and hydroxyproline in the sera, and the results are shown in Table 3 and Figures 5(a) – 5(d) . On days 14 and 28, the levels of protein concentration of TGF- β 1, CTGF, and hydroxyproline in BLM group were significantly higher when compared to that of control group ( p < 0.01), whereas the levels of protein concentration of CTGF and hydroxyproline in BLM+ Pred group were significantly higher than that of control group ( p <0.05). On day 28, the levels of protein concentration of TGF- β 1 and hydroxyproline in YYYQ-L group were significantly higher than that in the control group ( p <0.05) but were lower than that in BLM group ( p <0.05). On day 28, the levels of protein concentration of TGF- β 1, CTGF, and hydroxyproline in the sera samples of BLM+ Pred and BLM+YYYQ groups were significantly decreased compared to that of BLM group, especially in YYYQ-M and YYYQ-H groups ( p < 0.01 or p < 0.05). Table 3: Data of ELISA assay of each group on day 14 and 28 were presented as mean± SD. Compared with control group ( p <0.05, p <0.01), compared with BLM group ( p <0.05, p <0.01), compared with BLM + Pred group ( p <0.05, p <0.01), and compared with BLM + YYYQ-L group ( p <0.05, p <0.01). Figure 5: The secreted protein levels of TGF- β 1, CTGF, interleukin 18, and hydroxyproline in each group of rats on days 14 and 28.
On days 14 and 28, the levels of protein concentration of interleukin 18 in BLM group and BLM+YYYQ-L group were significantly higher than that in control group ( p < 0.01 or p 0.05). 3.3. YYYQ Inhibited BLM-Induced EMT in Rats
As shown in Table 4 and Figures 6(a) – 6(d) , the results indicated that, on day 14, compared with control group, the mRNA expression of α -SMA in BLM group was significantly higher ( p < 0.01), while the mRNA expression of E-cadherin was significantly lower ( p < 0.05). On day 28, the mRNA expression of α -SMA in BLM group and BLM + Pred group was significantly upregulated ( p < 0.01), whereas mRNA expression of E-cadherin was significantly downregulated ( p < 0.01). Treatment by prednisone and different dosage of YYYQ could reduce the mRNA expression of α -SMA compared with BLM only ( p <0.05 or p <0.01). Meanwhile, mRNA expression level of E-cadherin in BLM+ YYYQ-H group was significantly upregulated compared to BLM group ( p < 0.05), and it revealed more remarkable improvement than BLM+ Pred group ( p < 0.05). Table 4: Data of real-time PCR assay of each group on day 14 and 28 were presented as mean± SD. Compared with control group ( p <0.05, p <0.01), compared with BLM group ( p <0.05, p <0.01), compared with BLM + Pred group ( p <0.05, p <0.01), and compared with BLM + YYYQ-L group (△ p <0.05, △△ p <0.01). Figure 6: The mRNA expression of α -SMA, E-cadherin, laminin, and collagen I in each group of rats on days 14 and 28.
On both day 14 and day 28, mRNA expression of laminin and collagen I in BLM group, BLM + Pred group, and BLM + YYYQ-L group were significantly upregulated when compared to that of control group ( p < 0.05 or p < 0.01). In summary, mRNA expression of laminin in all the treatment groups were significantly downregulated compared to BLM group on both day 14 and day 28 ( p < 0.01); especially on day 28, mRNA level of laminin in different dosage of YYYQ group was significantly decreased compared with BLM + Pred group. The mRNA expression of collagen I in all the treatment groups was significantly downregulated when compared to that of BLM group ( p < 0.05 or p < 0.01). 3.4. YYYQ Suppressed BLM-Activated TGF- β 1/Smad Signaling Pathway in Rats
As indicated in Table 5 and Figures 7(a) – 7(e) , we observed that mRNA expression of TGF- β 1, T β RI, and T β RII in BLM, BLM+ Pred, and BLM+YYYQ-L group were significantly higher than that of control group on both day 14 and day 28 ( p <0.01 or p <0.05). On day 14, BLM+YYYQ-M and BLM+YYYQ-H group had downregulated mRNA expression of TGF- β 1, T β RI, and T β RII ( p <0.05). Meanwhile, mRNA expression of T β RII was significantly downregulated in YYYQ-M group than that of BLM + Pred group ( p <0.05). On day 28, the mRNA expression of TGF- β 1, T β RI, and T β RII in all treatment groups was significantly downregulated when compared to that in BLM group ( p <0.01). The overall results indicated that the BLM+YYYQ-H group had significant advantage over the BLM+ Pred and BLM+YYYQ-L group ( p <0.05). Table 5: Data of real-time PCR assay of each group on day 14 and 28 were presented as mean± SD. Compared with control group ( p <0.05, p <0.01), compared with BLM group ( p <0.05, p <0.01), compared with BLM + Pred group ( p <0.05, p <0.01), and compared with BLM + YYYQ-L group (△ p <0.05, △△ p <0.01). Figure 7: The mRNA expression of TGF- β 1, T β RI, T β RII, Smad3, and Smad7 in each group of rats on days 14 and 28.
On days 14 and 28, the mRNA expression of Smad3 in BLM and BLM+ Pred group was significantly upregulated ( p <0.05 or p <0.01), whereas mRNA level of Smad7 was significantly downregulated in BLM group when compared to that of control group ( p <0.01). BLM+YYYQ group could significantly downregulated the mRNA expression of Smad 3 than BLM group ( p <0.05 or <0.01). Moreover, the mRNA level of Smad 3 in BLM + YYYQ-M group and BLM + YYYQ-H group was lower than BLM + Pred group ( p < 0.05). Apart from that, the results also showed that mRNA expression of Smad 7 was significantly upregulated in all treatment groups, especially in BLM + YYYQ-M group ( p < 0.05). 4. Discussion
IPF is a chronic, progressive, and irreversible lethal lung disease, and the annual incidence of IPF is rising. The main clinical manifestations of pulmonary fibrosis are cough, scanty phlegm, wheezing, fatigue, cyanosis, acropachy, etc. It can cause massive deterioration to the quality of life among the patients. So far, IPF still lacks safe and effective therapeutic regimens in the clinic. From the perspective of Chinese medicine, the main pathogenesis during the early stage of IPF, also known as Feibi, is invasion of exogenous pathogens into the lungs as a result of deficiency of lung qi, which then lead to formation of blood stasis in the lungs. If left untreated, the disease will gradually progress into late stage, also known as Feiwei, which is marked by deficiency of qi and yin. YYYQ has the effects of nourishing yin and benefiting qi, promoting blood circulation and removing toxic substances. Thus, the indications of YYYQ coincide with the main pathogenesis of IPF, which is marked by the presence of blood stasis and deficiency of qi and yin.
YYYQ contains astragalus mongholicus, Codonopsis pilosula , radix scrophulariae, radix glehniae, rhizome polygonati, radix lithospermi, ligusticum wallichii, smoked plum, radices trichosanthis, and pericarpium citri reticulatae. It is reported that astragalus, the main ingredient of YYYQ, has various main active ingredients, such as astragaloside, total saponin of astragalus, and astragalus polysaccharides, which have the potential to regulate cell apoptosis and cell differentiation by regulating TGF- β /Smad, Wnt/ β -catenin, PI3K/Akt, and other signaling pathways in order to reduce oxidation, inflammation, and extracellular matrix deposition of the relative tissues [ 25 ]. Meanwhile, radix glehniae is reported to be able to enhance the phagocytosis of macrophages, increase the number of T lymphocytes, enhance the functions of immune system, and reduce the expression of collagens such as hydroxyproline, fibronectin, and laminin, which can be found in pulmonary fibrotic rats [ 26 , 27 ]. It is also found that other ingredients of YYYQ, such as radix lithospermi, can inhibit the expression of endothelial growth factors to reduce angiogenesis, thereby preventing the progression of pulmonary fibrosis [ 28 ], whereas ligustrazine can decrease TGF- β 1 and CTGF levels in pulmonary fibrotic rats [ 29 ].
In the present study, we used the classic method of intratracheal instillation of BLM to establish pulmonary fibrosis model of rats, the histopathologic changes, and molecular pathway of which are similar to human beings [ 30 ] and then intervention with the corresponding drugs occured. Then the protective effect of YYYQ on BLM-induced pulmonary fibrosis in rats by observing pathological changes and related protein and gene expression was investigated. The results of histopathological analysis showed that, during the early stage of pulmonary fibrosis, the main pathological manifestation of lung tissues was marked by alveolitis, which then developed into pulmonary fibrosis during the latter stage. On both day 14 and day 28, YYYQ has significantly reduced the degree of severity of alveolitis, which in turn delays the progression of alveolitis into pulmonary fibrosis, in which BLM + YYYQ-H group indicated better result compared to that of BLM + Pred group.
TGF- β 1 played a key role in the progression of pulmonary fibrosis by promoting proliferation and differentiation of fibroblasts, enhancing synthesis of collagen, and altering some components in EMC [ 31 ]. Smad proteins are the main signal transducers for TGF- β 1 signaling pathway [ 32 ], in which Smad3 binds to Smad 4 to form a complex and then make an entry into the nucleus in order to regulate the targeted gene transcription, which thereby interfere with the formation of lung fibrosis [ 33 ]. On the contrary, Smad7 inhibits pulmonary fibrosis by competitively binding to TGF- β 1 and its receptors complex with Smad3 [ 34 ].On both day 14 and day 28, it is discovered that the mRNA expression of TGF- β 1 and its receptors and Smad3 was significantly downregulated, while the mRNA expression of Smad7 was significantly upregulated. These results could hint the activation of TGF- β 1/Smad signaling pathway during the process of pulmonary fibrosis. Although both YYYQ and prednisone resulted in downregulation of mRNA expression of TGF- β 1 and its receptors and Smad3, as well as upregulation of Smad7, the results from the present studies indicated that BLM + YYYQ groups had a more significant treatment effect compared to that of BLM+ Pred group, which was consistent with histopathological results. The results above suggested that YYYQ could ameliorate the progression of PF by inhibiting TGF- β 1/Smad pathway in the lungs of pulmonary fibrotic rats.
TGF- β 1 is an important profibrotic factor, and CTGF is a direct downstream mediator of TGF- β 1. During the process of pulmonary fibrosis, the increase of TGF- β 1 induces the upregulation of CTGF, which promotes the proliferation and differentiation of fibroblasts and collagen production [ 35 ]. Although the role of interleukin 18 in the development of pulmonary fibrosis is yet to be conclusive, however, it is reported that interleukin 18 may act as a proinflammatory factor by secreting interleukin 1 β , tumor necrosis factor- α , and other cytokines, which can aggravate the damage to the lung tissues. Apart from that, interleukin 18 can also promote the secretion of cytokines, such as interferon- γ and interleukin 2 by Th1 cells, which then enhances type 1 hypersensitive responses to delay the further progression of pulmonary fibrosis [ 36 , 37 ]. The level of a specific amino acid found in collagen, known as hydroxyproline, could reflect the level of collagen fiber and ECM. The result of this study showed that YYYQ not only lower the protein concentration of TGF- β 1 and CTGF, but also can lower the protein concentration of hydroxyproline in the sera of BLM-stimulated rats. The data also reflected that YYYQ lowered the protein concentration of interleukin 18, but the difference was not statistically significant.
Studies found that TGF- β 1 can induce the process of EMT, which serve as an important pathogenesis in the development of pulmonary fibrosis [ 38 – 40 ]. Therefore, it can also be said that EMT can be suppressed by inhibiting the TGF- β 1/Smad signaling pathway in order to delay the progression of fibrosis-related diseases [ 41 ]. E-cadherin, as an epithelial phenotype marker, has the function of maintaining epithelial constitutive and polar protein. Meanwhile, α -SMA and Collagen I are interstitial marker protein, which are secreted by myofibroblasts [ 42 , 43 ], and they are main indicators of the content of extracellular matrix. During the process of EMT, the E-cadherin level is downregulated and the expression of α -SMA and Collagen I are upregulated [ 44 , 45 ]. Laminin has the effects of inducing, adhering, stimulating growth, and differentiation on cells. It can stimulate T lymphocytes and macrophages to secrete many inflammatory factors, thereby promoting the synthesis of collagen in fibroblasts [ 46 ]. In the early stage of pulmonary fibrosis, a large amount of laminin was deposited in the lung tissue, and the level of laminin is often positively correlated with the patient’s condition [ 47 ]. The experimental results revealed that YYYQ significantly reduced the mRNA expression of α -SMA and improved mRNA expression of E-cadherin when compared with BLM group on day 28, in which BLM+YYYQ-H group had better effect than BLM + Pred group. The mRNA expression of laminin and collagen I were both decreased in BLM+ Pred and BLM+YYYQ groups, but YYYQ groups exhibited better therapeutic effect than that of BLM + Pred group. The data from the present study suggested that YYYQ could inhibit TGF- β 1 mediated EMT, upregulate mRNA expression of α -SMA, and downregulate mRNA expression of E-cadherin in BLM-induced pulmonary fibrotic rats.
In conclusion, our study exhibited the effectiveness of YYYQ in delaying the progression of pulmonary fibrosis. However, there were several limitations encountered in this study. For example, on day 14, YYYQ had no significant effect on the mRNA expression of α -SMA, E-cadherin, Collagen I, and CTGF, but the therapeutic effect of each index was better on day 28. The reason may be that YYYQ has better therapeutic effects during the latter stage of pulmonary fibrotic rats. This may be due to the latter stage of pulmonary fibrosis, which is marked by increased lung fibers, and reduction in lung capacity has a closer resemblance to the concept of Feiwei in Chinese medicine. As mentioned earlier, Feiwei is a state in which the main pathogenesis is highlighted by deficiency of qi and yin, as well as presence of blood stasis. Hence, the treatment principles of pulmonary fibrosis are nourishing yin and qi and promoting blood circulation, which are in line with the therapeutic effects of YYYQ. Besides, the results also indicated that YYYQ did not reduce the protein concentration of interleukin 18 significantly. From the perspective of Chinese medicine, the pathological state of toxic-heat resembles the state of inflammation. It is postulated that interleukin 18, a proinflammatory cytokine, is not affected by YYYQ significantly, because this decoction contains few herbs which carry the effect of clearing heat and detoxification. This may be also due to the limited role played by interleukin 18 in the process of pulmonary fibrosis; thus, the effect of YYYQ on interleukin 18 is less significant. Our future perspective is to further study the mechanisms on how YYYQ could inhibit TGF- β 1/Smad signaling pathway in BLM-induced pulmonary fibrotic rats. 5. Conclusion
In summary, the result of our study concluded that YYYQ could alleviate the severity of alveolitis and fibrosis on BLM-induced pulmonary fibrosis in rats, inhibit the mRNA expression of TGF- β 1 and its receptors, Smad3, α -SMA, and CTGF, enhance mRNA expression of Smad7 and E-cadherin, and reduce the mRNA expression of collagen such as laminin, collagen I, and hydroxyproline, but the effect on interleukin 18 was not obvious. In other words, YYYQ has the potential of ameliorating progression of pulmonary fibrosis, and the mechanism may be related to suppressing TGF- β 1/Smad signal pathway and EMT in BLM-induced pulmonary fibrosis of rats. Abbreviations

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