Acute Disorders

• Respiratory Depression
• Respiratory Syncytial Virus (RSV)
• Acute Respiratory Distress Syndrome (ARDS)

• Mucociliary Clearance and Dysfunction
• Pneumonia
• Cough

• Tuberculosis (TB)
• Bronchiolitis
• Bronchitis

Respiratory Depression

Hypoventilation or bradypnea (also known as respiratory depression) occurs when ventilation is inadequate to perform needed gas exchange. This causes an increased concentration of carbon dioxide (hypercapnia) and respiratory acidosis (a low blood pH) which can lead to lethargy, coma, and death. Causes of respiratory depression include medications such as opioid narcotics (both prescription and illicit drugs), barbiturates, or sedatives, alcohol, tumors, metabolic disorders, neuromuscular diseases, or airway obstruction. Opioid overdose deaths are at record high levels in the United States where over 78 deaths occur each day. Enhanced funding and research efforts to curtail opioid abuse, addiction, and overdose are at the forefront of government initiatives to address this growing critical health crisis.

Watch this webinar where experts discuss physiological mechanisms behind the opioid epidemic and present their research on the effects of opioids on sleep and respiratory depression in preclinical mouse models.

References using whole body plethysmography solutions to study respiratory depression: 

Kuo A, Wyse B, Meutermans W, Smith T. “In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile.” British Journal of Pharmacology. 2015; 172:532-548.

Zadina JE, Nilges MR, Morgenweck J, Zhang X, Hackler L, Fasold MB. “Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine.” Neuropharmacology. 2016; 105:215-227.

Morse BL, Vijay N, Morris ME. “γ-Hydroxybutyrate (GHB)-induced respiratory depression: combined receptor-transporter inhibition therapy for treatment in GHB overdose.” Molecular Pharmacology. 2012; 82(2):226-235.

Webinar: Understanding Physiological Mechanisms of Opioid Addiction: Advancements in CNS and Respiratory Endpoint Measurement

Respiratory Syncytial Virus (RSV)

Respiratory syncytial virus (RSV) is a common virus that infects the respiratory tract and lungs. Most people develop mild cold symptoms with RSV infection that resolve within 1 to 2 weeks, but young children, older adults, and those with weakened immune systems can have more serious and prolonged symptoms. Lower respiratory tract infection with RSV causes increased mucus production and epithelial lining edema and necrosis, leading to airway obstruction, air trapping, and increased airway resistance. Nearly all children are infected with RSV by the age of 2 years, and it is the leading cause of bronchiolitis and pneumonia in infants. Asthma exacerbations are common with viral infections like RSV, and recent evidence suggests that RSV infection at a young age is linked to recurrent wheezing or asthma in later childhood and adolescence. Risk factors for acquiring RSV infection include daycare attendance, contact with school-aged siblings, crowded living conditions, low socioeconomic status, smoke exposure, multiple birth sets (triplets or greater), and minimal breastfeeding.

References using whole body plethysmography and non-invasive airway mechanics solutions to study RSV:

Khaitov M, Shilovskiy I, Nikonova A, Shershakova N, Kamyshnikov O, Babakhin A, Zverev V, Johnston S, Khaitov R. “Small interfering RNAs targeted to interleukin-4 and respiratory syncytial virus reduce airway inflammation in a mouse model of virus-induced asthma exacerbation.” Human Gene Therapy. 2014;25:642-650.

Stark J, Khan A, Chiappetta C, Xue H, Alcorn J, Colasurdo G. “Immune and Functional Role of Nitric Oxide in a Mouse Model of Respiratory Syncytial Virus Infection.” Journal of Infections Disease. 2005;191:387-95.

Phipps S, Lam C, Mahalingam S, Newhouse M, Ramirez R, Rosenberg H, Foster P, Matthaei K. “Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus.” Blood. 2007;110:1578-86.

Acute Respiratory Distress Syndrome (ARDS)

Acute respiratory distress syndrome (ARDS) is a rapidly progressive inflammatory reaction that affects the lungs in the critically ill population. A traumatic event, such as sepsis, near-drowning, excessive smoke inhalation, severe pneumonia, or shock, causes blood vessels in the lungs to leak fluid into the air sacs (alveoli). Gas exchange is impaired and the lungs become difficult to inflate, leading to respiratory failure. Some patients develop scarring (fibrosis) or a collapsed lung (pneumothorax). Treatment includes ventilator support, prone positioning, sedation and paralytics, and diuretics. About 200,000 cases of ARDS occur each year in the United States. Death occurs in 30% to 50% of those affected (usually from kidney, liver, or circulatory failure), and those who survive usually have long hospital stays and recovery times. Survivors regain most of their lung function. Risk factors for developing ARDS include cigarette smoking, obesity, recent surgery, oxygen use for pre-existing lung condition, alcohol abuse, and recent chemotherapy.

References using whole body plethysmography and pulmonary function testing solutions to study ARDS:

Ortolan L, Sercundes M, Barboza R, Debone D, Murillo O, Hagen S, Russo M, Lima M, Alvarez J, Amaku M, arinho C, Epiphanio S. “Predictive Criteria to Study the Pathogenesis of Malaria-Associated ALI/ARDS in Mice.” Mediators of Inflammation. 2014; Article ID 872464.

Wu N, Wang J. “Curcumin Attenuates Liver Warm Ischemia and Reperfusion–Induced Combined Restrictive and Obstructive Lung Disease by Reducing Matrix  etalloprotease 9 Activity.” Transplantation Proceedings. 2014; 46(4): 1135-1138.

Mucociliary Clearance and Dysfunction

Mucociliary clearance is an important primary innate defense mechanism that protects the lungs from the effects of inhaled pollutants, allergens, and pathogens. Mucus cleanses the nose and throat by flushing out invading microorganisms and pollutants through its constant movement down the upper respiratory tract. Mucociliary clearance consists of cilia in the right quantity and of the right length beating vigorously in a set pattern in a fluid layer in the airways. This fluid layer is topped by mucus of a very specific stickiness and amount that traps debris and pathogens. The ciliary activity underneath this sticky mucus moves the mucus toward the mouth where it can be coughed out or swallowed. Together, properly functioning cilia, mucus of the right stickiness and quantity, and a vigorous cough provide an important line of defense for the lungs.

Mucociliary dysfunction can occur in a variety of chronic airway diseases. When mucociliary clearance is impaired, the lungs are not able to effectively remove inhaled particles. Sensing the presence of unwanted elements, the lungs increase the production of mucus to flush them out. If the mucus cannot be moved because it is too sticky (as in cystic fibrosis or CF), the cilia aren’t beating (as in primary ciliary dyskinesia or PCD) or cough is impaired (as in a number of neuromuscular disorders), a vicious cycle of mucus over-production, inflammation and infection occurs. In time, repeated and chronic infections cause irreversible damage to the airways (a condition known as bronchiectasis), and the cycle continues to get more severe. In PCD and CF, the mucociliary clearance system is profoundly damaged from birth. In PCD, cough is generally spared, which may explain why lung damage in PCD usually progresses more slowly than in CF. In CF, extremely sticky mucus creates an ineffective cough, so all components of primary lung defense are impaired. In both disorders, bronchiectasis is nearly universal and as it progresses, more serious infections with drug-resistant bacteria become common.

Mucociliary dysfunction can also occur with acute infections such as pertussis (whooping cough).Bordetella pertussis attaches to cilia of the respiratory epithelium, produces toxins that paralyze the cilia, and causes inflammation and damage to the respiratory tract. Pulmonary secretions are inadequately cleared and patients develop paroxysmal coughing (numerous, rapid coughing) followed by the characteristic high-pitched “whoop” upon inspiration. This can occur for 6-10 weeks before gradual recovery.

References using pulmonary function testing and whole body plethysmograph solution to study mucociliary dysfunction: 

Rajavelu P, Chen G, Xu Y, Kitzmiller J, Korfhagen T, and Whitsett J. ” Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation.” Journal of Clinical Investigation. 2015;125(5):2012-2031

Marcos V, Zhou-Suckow Z, Yildirim A, Bohla A, Hector A, Vitkov L, Krautgartner W, Stoiber W, Griese M, Eickelberg O, Mall M, Hartl D. “Free DNA in Cystic Fibrosis Airway Fluids Correlates with Airflow Obstruction.” Mediators of Inflammation. 2015.

Pneumonia

Pneumonia is a lower respiratory infection that causes inflammation of the air sacs (alveoli) in one or both lungs. The alveoli fill with fluid or pus (purulent material), causing cough with phlegm (productive cough), fever, chills, shortness of breath, chest pain, or fast breathing. A variety of organisms, including bacteria, viruses and fungi, can cause pneumonia. Its severity ranges from mild to life-threatening, but most healthy people recover from the infection within 1 to 3 weeks. Each year, about one million people are hospitalized in the United States for pneumonia with approximately 50,000 deaths. Globally, it is the leading cause of death in children under 5 years of age with nearly 1 million deaths per year. Risk factors for developing pneumonia include chronic lung diseases such as asthma or COPD, diabetes, heart failure, smoke exposure, dysphagia (difficulty swallowing), alcoholism, neurologic deficits that impair the cough reflex, and long-term use of acid-suppressing medications such as proton pump inhibitors or H2-blockers. Pneumonia is most serious for infants and young children, people older than age 65, and people with health problems or weakened immune systems. These patients are at risk for developing complications such as empyema (infected fluid in the pleural space surrounding the lung), lung abscesses, respiratory failure, or sepsis.

References using resistance and compliance solutions and pulmonary function testing solutions to study pneumonia: 

Zhang ZQ, Wang J, Hoy Z, Keegan A, Bhagwat S, Gigliotti F, Wright TW. “Neither classical nor alternative macrophage activation is required for Pneumocystis clearance during immune reconstitution inflammatory syndrome.” Infect Immun. 2015;83:4594-603.

Kling H, Shipley T, Guyach S,  Tarantelli R, Morris A, Norris K. “Trimethoprim-Sulfamethoxazole Treatment Does Not Reverse Obstructive Pulmonary Changes in Pneumocystis-Colonized Non-Human Primates with SHIV Infection.” J Acquir Immune Defic Syndr. 2014; 65(4):381-389.

Cough

A cough is the body's way of removing foreign material or mucus from the respiratory tract or responding when something irritates the throat or airways. An irritant stimulates nerves that send a message to the brain which then tells muscles in the chest and abdomen to push air out of the lungs to force out the irritant. A cough can be productive (mucus producing) or nonproductive (dry, hacking). Cough is only a symptom and not a disease itself. An occasional cough is normal and healthy; viral respiratory infections are the most common cause of cough that lasts less than 3 weeks. A cough that persists for several weeks or one that brings up discolored or bloody mucus may indicate a condition that needs medical attention. Causes of chronic cough (> 8 weeks) include allergies or post-nasal drip, pertussis, asthma, smoking/COPD, cystic fibrosis, gastroesophageal reflux disease, lung tumors, heart failure, or certain medications like ACE inhibitors.

References using whole body plethysmography solutions to study cough: 

Song K, Shin Y, Lee K, Lee E, Suh Y,Kim K. “Expectorant and Antitussive Effect of Hedera helix andRhizoma coptidis Extracts Mixture.” Yonsei Medical Journal. 2015;56(3):819-824.

Wex E, Bouyssou T. “Olodaterol Attenuates Citric Acid-Induced Cough in Naïve and Ovalbumin-Sensitized and Challenged Guinea Pigs”. PLoS One. 2015; 10(3).

Tuberculosis (TB)

Tuberculosis (TB) is a potentially fatal infectious disease caused by a bacterium called Mycobacterium tuberculosis (M. tuberculosis). The bacteria usually infect the lungs but can attack any part of the body including the kidney, spine, and brain; this is more common in young children or those with weakened immune systems. Most people infected with TB do not have symptoms (latent TB) but if they are not treated, about 10% will develop active disease. Nearly 10 million people have active disease worldwide and about 1.5 million will die from the infection, mostly in developing countries. Active infection in the lungs is characterized by a chronic cough with blood-tinged mucus, fever, night sweats, and weight loss. This highly contagious disease is spread through the air when a person with active pulmonary infection coughs, sneezes, spits, or speaks. Risk factors for developing TB include HIV, overcrowded conditions, malnutrition, chronic lung disease, smoke exposure, and exposure to immunosuppressant medications such as corticosteroids and anti-TNF antibodies. Antibiotics are used to treat latent and active TB infections, but therapy can take several months. Combinations of antibiotics are used to prevent resistance development, but multi-drug resistant strains are on the rise.

Vaccine research relies on the ability to properly expose test subjects to the M. tuberculosis strain. The use of head out plethysmographs, masks, or helmets from DSI enables the aerosol to be delivered simultaneously with the measurement of respiration rate and tidal volume. This helps create a reproducible and more accurate delivery method to the lungs. 

References using head out plethysmograph solutions to study tuberculosis: 

Sibley L, Dennis M, Sarfas C, White A, Clark S, Gleeson F, McIntyre A, Rayner E, Pearson G, Williams A, Marsh P, Sharpe S. “Route of delivery to the airway influences the distribution of pulmonary disease but not the outcome of Mycobacterium tuberculosis infection in rhesus macaques.” Tuberculosis. 2016;96:141-149.

Sharpe S, McShane H, Dennis M, Basaraba R, Gleeson F, Hall G, McIntyre A, Gooch K, Clark S, Beveridge N, Nuth E, White A, Marriott A, Dowall S, Hill A, Williams A, Marsh P. “Establishment of an Aerosol Challenge Model of Tuberculosis in Rhesus Macaques and an Evaluation of Endpoints for Vaccine Testing.”Clinical and Vaccine Immunology. 2010;17:1170-1182.

Bronchiolitis

Bronchiolitis is an acute inflammation of the bronchioles (smallest air passages of the lungs) usually caused by respiratory viral infections during the winter and spring months. It primarily affects children younger than 2 years with the majority of cases seen between 3 and 6 months of age. About 20 percent of infants in the United States get bronchiolitis each year. Blockage of airflow occurs in small inflamed airways and, in conjunction with increased mucus production and damage to the epithelial lining, leads to wheezing, coughing, and difficulty breathing and feeding. Most children have mild symptoms that resolve completely within 8 to 15 days, but some children experience severe disease and may require hospitalization or mechanical ventilation for respiratory failure. Airway hyperresponsiveness may be present for several weeks after the acute infection, leading to recurrent cough and wheeze. Some evidence suggests that there is a link between bronchiolitis in infancy and the development of recurrent wheezing or asthma throughout childhood and adolescence. Risk factors for developing bronchiolitis include prematurity, chronic lung disease, congenital heart disease, smoke exposure, daycare attendance, neuromuscular disease, lack of breastfeeding, and low socioeconomic status.

References using double chamber plethysmography solutions to study bronchiolitis:

Glineur S, Anh D, Sarlet M, Michaux C, Desmecht D. “Characterization of the Resistance of SJL/J Mice to Pneumonia Virus of Mice, a Model for Infantile Bronchiolitis Due to a Respiratory Syncytial Virus.” PLoS ONE. 2012;7(10): e44581. doi:10.1371/journal.pone.0044581

Bronchitis

Acute bronchitis is an inflammation of the lining of the bronchial tubes caused mainly by respiratory viral infections. It affects over 4% of people in the United States, usually in the fall and winter months. Airway hyperresponsiveness and increased mucus production contribute to the symptoms for which patients seek medical care: cough, thickened mucus, chest tightness, wheezing, and fatigue. Viral infections resolve spontaneously within 10 days, but cough can continue for several weeks. Up to 80% of patients diagnosed with acute bronchitis are inappropriately prescribed an antibiotic which contributes to bacterial resistance and unnecessary side effects. Complications from bronchitis such as pneumonia or respiratory failure are uncommon but are more likely to occur in those with weakened immune systems, age extremes, major health conditions affecting the cardiovascular or pulmonary system including smoke exposure, or lack of certain vaccinations. Some evidence suggests that previously healthy patients develop chronic bronchitis or asthma within 3 years of an initial acute bronchitis episode, but it is unclear if acute bronchitis predisposes patients to these conditions or if it is a marker for predisposition to chronic lung disease.