INFLAMMATION ASSOCIATED CHRONIC DISEASES: A TIME TO REEVALUATE OUR MEDICAL APPROACHES

I remember that day clearly, at a clinic for indigenous people. The doctor to whom I was speaking was a Pakistani, who was working in that remote location, fulfilling requirements for a visa to the USA.

What do you think, Dr? I asked him, what if Type 2 Diabetes turns out to be an inflammatory disease ? What if measured serum cholesterol is just a marker for the inflammation rather than any genetic abnormality of metabolism. He was distinctly annoyed and brushed me off saying that the physiology of Type 2 DM is well worked out: it is a combination of Insulin Resistance and Beta cell failure brought by Glucotoxicity. End of conversation. Of course, by then I was no longer subscribing to the body as a machine model physiological explanation.

I had always been interested in the history of Medicine. While we no longer have flamboyant character like a Dupuytren or an erudite man like Paget (each of  his six scientific papers are about diseases that bear his name, six of them), the new heroes are those who sit in the laboratories and toil away and publish in journals that very few practicing clinicians read, such as CELL. While the majority of journals are written in English language, as a colleague at University of Miami once remarked, who wants to read a scientific article from India or China?

Dr Eric Reiss, an Austrian pianist who was also an Endocrinologist taught us about the social importance of high cholesterol and I decided to look up the history of high cholesterol which is not familial in the USA and was surprised to find that it was of recent prevalence. Something in the society has made Hypercholesteroloemia prevalent, I thought, along with other socially dependent illnesses: Obesity, type 2 Diabetes. I thought of them as Social Inflammatory Diseases. (thanks to my Anthropological training in London)

You better start reading scientific articles from China or from Chinese authors. This was brought forth when looking through articles on Inflammation in the body and its consequences. Many papers had been published about it in the last few years and the majority of them had Chinese origin.

An example.

An article on Inflammasome published in October 2019

The location of the science was

·       ¹Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

·       ²Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

·       ³CAS Center for Excellence in Molecular Cell Science, Shanghai, China

From the same article:

Inflammasomes play a crucial role in innate immunity by serving as signaling platforms which deal with a plethora of pathogenic products and cellular products associated with stress and damage. By far, the best studied and most characterized inflammasome is NLRP3 inflammasome, which consists of NLRP3 (nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3), ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and procaspase-1. Activation of NLRP3 inflammasome is mediated by highly diverse stimuli. Upon activation, NLRP3 protein recruits the adapter ASC protein, which recruits the procaspase-1 resulting in its cleavage and activation, inducing the maturation, and secretion of inflammatory cytokines and pyroptosis. However, aberrant activation of the NLRP3 inflammasome is implicated in various diseases including diabetes, atherosclerosis, metabolic syndrome, cardiovascular, and neurodegenerative diseases; raising a tremendous clinical interest in exploring the potential inhibitors of NLRP3 inflammasome. 

NLRP3 Inflammasome Associated Diseases

Anomalous NLRP3 inflammasome activation is linked with the development of many diseases, especially age-associated ailments for example various metabolic syndromes and metabolic disorders including gout (16), atherosclerosis (35), Alzheimer's disease (AD) (11), and type II diabetes (T2D) (36). Enhanced secretion of IL-1β and IL-18 by NLRP3 inflammasome is associated with the progression of atherosclerotic plaque in atherosclerotic patients and animal models (37–39). NLRP3 inflammasome is involved in experimental autoimmune encephalomyelitis (EAE) in animal models and multiple sclerosis (MS) in humans (40, 41). Inappropriate NLRP3 inflammasome activation is also implicated in Crohn's disease, inflammatory bowel disease (IBD), and ulcerative colitis (42–44). NLRP3 inflammasome is also linked with various cancers, such as colon cancer, breast cancer, melanoma, hepatitis C virus-associated hepatocellular carcinoma, and gastrointestinal cancers (45, 46). In addition to NLRP3 activation anomalies, there are also NLRP3 genetic abnormalities collectively termed as cryopyrin-associated periodic syndromes (CAPS). Gain of function mutations in NLRP3 gene give rise CAPS disorders, resulting in enhanced IL-1β secretion, and other CAPS specific symptoms (47). (the numbers in parenthesis refer to the reference articles)

For those medical practitioners at the level of Primary Care ( Doctors as well as mid-level)) who look after many of these inflammatory diseases, there has to be a change in their way of thinking, from a machine model of fixing the body but act a counsellor to complement with pharmacological and non-pharmacological (mainly) actions.

I personally feel vindicated that my way of thinking which had its origin in my anthropological education, is now accepted widely.

In that journey I noticed that the persons who easily understood the concept and acted upon it were : Nurses, Nutritionists, Health educators and clinicians whose practices were not monetarily oriented and scientifically curious.

 For my scientifically curious friends: Perhaps this is the reason why Fluoxetine has been empirically used for Peripheral Neuropathy of Diabetes ? What do you think 

 Our findings reveal that fluoxetine confers an antidepressant effect partly through inhibition of peripheral and central NLRP3 inflammasome activation and suggest the potential clinical use of fluoxetine in NLRP3 inflammasome-driven inflammatory diseases such as depression.

Fluoxetine Inhibits NLRP3 Inflammasome Activation: Implication in Depression

Ren-Hong Du, MD, PhD, Jun Tan, MD, Xi-Yang Sun, MD, Ming Lu, MD, PhD, Jian-Hua Ding, MD, and Gang Hu, MD, PhD

(Pleease note the nationality of the authors)