Researchers discovered a new way to stop harmful inflammation in the lungs due to sepsis and injury

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University of Calgary researchers at the Cumming School of Medicine (CSM) led by Drs. Donna Senger, Ph.D., Paul Kubes, Ph.D., and Stephen Robbins, Ph.D. have discovered a new way to stop harmful inflammation in the lungs due to sepsis and injury.

“This work demonstrates the power of collaboration in solving complex health issues to benefit patients,” says Robbins, a professor in the departments of Oncology, and Biochemistry & Molecular Biology and Scientific Director of the CIHR Institute of Cancer Research.

“The research involved teams from 10 laboratories, nine at UCalgary with investigators from the Arnie Charbonneau Cancer Institute and the Snyder Institute for Chronic Diseases.”

One in 18 deaths in Canada is connected to sepsis. It occurs when the body is fighting off severe infection.

The immune system goes into overdrive sending white blood cells to clear up the infection.

The battle between your immune system and the infection leads to inflammation.

A problem occurs when the white blood cells leave the blood stream and move into the tissue to clean up the inflammation.

In some cases instead of cleaning up and moving on, they stay, and more white blood cells come in behind them.

The accumulation causes damage to internal organs, like the lungs, and can lead to death.

Sepsis is not the only condition that leads to an unhealthy collection of white blood cells in the lungs.

Inflammation caused by injury, and other diseases, can also create this harmful response. Acute lung injury is a leading cause of death in critical care in Canada.

The collaboration began about 15 years ago.

It was a project based on a similar premise, with two distinct problems to solve. The researchers wanted to know what was causing some cells to bind in the lungs.

Senger and Robbins are cancer biologists and were investigating how cancer metastasizes. They knew that some cancer cells target the lungs and somehow stay there and grow.

Many people with cancerous tumours do not die from the primary tumour, but rather from where the cancer metastasizes.

Meanwhile, Kubes, a specialist in inflammation was investigating why white blood cells collect in the lungs.

In conditions like sepsis, victims often die from the body’s response to the illness, not from sepsis itself.

Together they started screening for a molecule present in both processes.

They targeted the lining of blood vessels in the lungs because they suspected a signal would be present that allows cancer cells and white blood cells to stop and collect there.

That’s exactly where they found a molecule present during inflammation that could bind with white blood cells and help the cells pass from the blood stream into the tissue.

As long as those molecules are present, white blood cells continue to bind them.

Once the scientists understood how and why the white blood cells were entering the tissue, they went in search of an “off switch” to stop the molecule from binding with the white blood cell.

The teams developed a drug-like molecule that when introduced into the blood stream prevents white blood cells from binding with the molecule.

“We discovered that by targeting this molecule we can stop the ill effects of sepsis, acute lung injury and death,” says Kubes, the director of the Snyder Institute for Chronic Diseases at the CSM and professor in the Department of Physiology and Pharmacology.

“It could have an impact on any inflammatory condition in which lung injury is a contributor to worsening a patient’s condition.”

With this knowledge, the researchers have found a similar process that occurs in the liver.

They’ve now patented two drug-like molecules that can prevent lung and liver damage due to inflammation.

While all of the research to date has been performed on mice, a phase I clinical trial is underway to begin human testing.

The researchers are also applying the findings to cancer metastasis in hopes this new understanding could lead to treatments to stop cancer cells from spreading in the body and targeting the liver and lungs.

“The molecule we discovered binds to both white blood cells and certain cancer cells,” says Senger, a research associate professor in the Department of Oncology.

“We’ve developed a way to stop the white blood cells from binding and moving into the tissue. Now, we’re hoping to find a solution to prevent cancer cells from spreading to these organs.”

More information: Saurav Roy Choudhury et al, Dipeptidase-1 Is an Adhesion Receptor for Neutrophil Recruitment in Lungs and Liver, Cell(2019). DOI: 10.1016/j.cell.2019.07.017

Journal information: Cell
Provided by University of Calgary


Inflammation is part of the body’s defense mechanism.

It is the process by which the immune system recognizes and removes harmful stimuli and begins the healing process. There are generally two types of inflammation: acute and chronic inflammation.[1][2][3]

Acute Inflammation

Tissue damage due to trauma, microbial invasion, or noxious compounds all induce acute inflammation. It starts rapidly, becomes severe in a short time and symptoms may last for a few days for example cellulitis or acute pneumonia. Subacute inflammation is the period between acute and chronic inflammation and may last 2 to 6 weeks.

Chronic Inflammation

Chronic inflammation is also referred to as slow, long-term inflammation lasting for prolonged periods of several months to years. Generally, the extent and effects of chronic inflammation vary with the cause of the injury and the ability of the body to repair and overcome the damage. This article reviews chronic inflammation.

Etiology

Chronic inflammation can result from the following:

  1. Failure of eliminating the agent causing an acute inflammation such as infectious organisms including Mycobacterium tuberculosis, protozoa, fungi, and other parasites that can resist host defenses and remain in the tissue for an extended period.
  2. Exposure to a low level of a particular irritant or foreign materials that cannot be eliminated by enzymatic breakdown or phagocytosis in the body including substances or industrial chemical that can be inhaled over a long period, for example, silica dust.
  3. An autoimmune disorder in which the immune system is sensitized to the normal component of the body and attacks healthy tissue giving rise to diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE).
  4. Recurrent episodes of acute inflammation. However, in some cases, chronic inflammation is an independent response and not a sequel to acute inflammation for example diseases such as tuberculosis and rheumatoid arthritis.
  5. Inflammatory and biochemical inducers are causing oxidative stress and mitochondrial dysfunction such as increased production of free radical molecules, advanced glycation end products (AGEs), uric acid (urate) crystals, oxidized lipoproteins, homocysteine, and others.

Epidemiology

Chronic inflammatory diseases are the most significant cause of death in the world. The World Health Organization (WHO) ranks chronic diseases as the greatest threat to human health. The prevalence of diseases associated with chronic inflammation is anticipated to increase persistently for the next 30 years in the United States. in 2000, nearly 125 million Americans were living with chronic conditions and 61 million (21%) had more than one. In recent estimates by Rand Corporation, in 2014 nearly 60% of Americans had at least one chronic condition, 42% had more than one and 12% of adults had 5 or more chronic conditions. Worldwide, 3 of 5 people die due to chronic inflammatory diseases like stroke, chronic respiratory diseases, heart disorders, cancer, obesity, and diabetes. [4][5][6]The prevalence of some specific chronic inflammation-mediated diseases are as follows:

  • DiabetesAccording to American Diabetes Association, 30.3 million people or 9.4% of the American population, had diabetes in 2015 and it was the 7th leading cause of death in the United States.
  • Cardiovascular diseases: In line with 2017 updated report from the American Heart Association, cardiovascular diseases (CVDs) accounts for 1 out of every three deaths or approximately 800,000 deaths in the United States. Globally, CVD accounts for 31% of all deaths, and coronary heart disease (CHD) accounts for most deaths due to CVD, followed by stroke (1 of 20 deaths in the United States) and heart failure.
  • Arthritis and Joint Diseases: These affect approximately 350 million people worldwide and nearly 43 million people in the United States or almost 20% of the population. This number is expected to exceed 60 million by 2020. Nearly, 2.1 million Americans suffer from rheumatoid arthritis.
  • Allergies: These rank among the sixth leading cause of chronic human diseases in the United States and affect more than 50 million Americans each year. Asthma affects more than 24 million people in the United States including more than 6 million children. In 2015, 8.2% of adults and 8.4% of children were diagnosed with hay fever.
  • Chronic Obstructive Pulmonary Disease (COPD): The third most common cause of death in the United States in 2014, and nearly 15.7 million Americans (6.4%) were reported to have been diagnosed with COPD.

Pathophysiology

Most of the features of acute inflammation continue as the inflammation becomes chronic, including expansion of blood vessels (vasodilation), increase in blood flow, capillary permeability and migration of neutrophils into the infected tissue through the capillary wall (diapedesis). However, the composition of the white blood cells changes soon and the macrophages and lymphocytes begin to replace short-lived neutrophils. Thus the hallmarks of chronic inflammation are the infiltration of the primary inflammatory cells such as macrophages, lymphocytes, and plasma cells in the tissue site, producing inflammatory cytokines, growth factors, enzymes and hence contributing to the progression of tissue damage and secondary repair including fibrosis and granuloma formation, etc.[7][8][9][10]

Types of Chronic Inflammation 

  • Nonspecific proliferative: Characterized by the presence of non-specific granulation tissue formed by infiltration of mononuclear cells (lymphocytes, macrophages, plasma cells) and proliferation of fibroblasts, connective tissue, vessels and epithelial cells, for example, an inflammatory polyp-like nasal or cervical polyp and lung abscess.
  • Granulomatous inflammation: A specific type of chronic inflammation characterized by the presence of distinct nodular lesions or granulomas formed with an aggregation of activated macrophages or its derived cell called epithelioid cells usually surrounded by lymphocytes. The macrophages or epithelioid cells inside the granulomas often coalesce to form Langhans or giant cells such as foreign body, Aschoff, Reed-Sternberg and Tumor giant cells. There are two types:
  1. Granuloma formed due to a foreign body or T-cell mediated immune response is termed as foreign body granuloma, for example, silicosis
  2. Granuloma that are formed from chronic infection is termed as infectious granuloma, for example, tuberculosis and leprosy.

History and Physical

Risk Factors Associated with Chronic Inflammation

Several risk factors promote low-level inflammatory response. These include:

  • Age: Increasing age is positively correlated with elevated levels of several inflammatory molecules. The age-associated increase in inflammatory molecules may be due to mitochondrial dysfunction or free radical accumulation over time and other age-related factors like increase in visceral body fat.
  • Obesity: Many studies reported that fat tissue is an endocrine organ, secreting multiple adipokines and other inflammatory mediators. Some reports show that body mass index of an individual is proportional to the amount of pro-inflammatory cytokines secreted. Metabolic syndrome typifies this well.
  • Diet: Diet rich in saturated fat, trans-fats, or refined sugar is associated with higher production of pro-inflammatory molecules, especially in individuals with diabetes or overweight individuals.
  • Smoking: Cigarette smoking is associated with lowering the production of anti-inflammatory molecules and inducing inflammation.
  • Low Sex Hormones: Studies show that sex hormones like testosterone and estrogen can suppress the production and secretion of several pro-inflammatory markers and it has been observed that maintaining sex hormone levels reduces the risk of several inflammatory diseases.
  • Stress and Sleep Disorders: Both physical and emotional stress is associated with inflammatory cytokine release. Stress can also cause sleep disorders. Since individuals with irregular sleep schedules are more likely to have chronic inflammation than consistent sleepers, the sleep disorder is also considered as one of the independent risk factors for chronic inflammation.

Symptoms of Chronic Inflammation

Some of the common signs and symptoms that develop during chronic inflammation are listed below.

  • Body pain
  • Constant fatigue and insomnia
  • Depression, anxiety and mood disorders
  • Gastrointestinal complications like constipation, diarrhea, and acid reflux
  • Weight gain
  • Frequent infections

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