Airway Epithelial Injury, Acquired Ciliary Defects, and Non-PCD Mucociliary Pathology and Dysfunction

Introduction

Numerous studies have documented the mechanisms of acute injury to the epithelial cells comprising the mucociliary escalator. Among otherwise healthy individuals, acute epithelial injury from naturally acquired respiratory infections, intermittent exposures to irritants and pollutants in the ambient air, and host inflammatory responses to injury may result in morphologically evident changes that can be associated with transient functional decrements in mucociliary clearance and general respiratory health. Recovery from occasional acute respiratory infections, which may require supportive and antibiotic therapy, and the removal of injurious stimuli in the case of air pollutants and irritants is generally sufficient for normal airway epithelial organization to be re-established However, recurrent infections and/or continuing exposure to airborne gases and particulates can result in remodeling of the airway epithelial architecture in a way that may lead to persisting changes and severe adverse respiratory health effects and death.

Some Common Respiratory Infectious Agents and Their Effects on Cilia and Mucociliary Function

Acute respiratory disease resulting from bacterial and viral infections is a major cause of physician visits particularly among pediatric populations, thus making it a major health management and economic issue. The major respiratory infectious agents causing acute disease in humans can be divided into three broad groups:

  1. viruses
  2. bacteria
  3. mycoplasmas

Viruses

Viruses are intracellular parasites that can pass through conventional bacteriological filters. They contain a virus-specific nucleic acids but require the synthetic machinery of a host cell for replication and proliferation. Common respiratory viruses include the influenza viruses, respiratory syncytial virus, adenoviruses, and rhinoviruses. Viruses are associated with the "common cold" and with the "flu" and are often the agents of pneumonia, bronchiolitis, and inner ear infections (otitis). Antibiotics are ineffective against viruses although there are some chemotherapeutic agents which may limit the severity of illness by suppressing viral replication. However, the suppression of mucociliary clearance mechanisms during viral infection may create an environment in the respiratory tract conducive to the development of a subsequent bacterial infection requiring antibiotic therapy.

Pictured below are electron micrographs of some viruses which may cause respiratory infections

This view of type a influenza virus shows several virions (one is circled) attached to an infected ciliated epithelial cell.

Electron micrographs of viruses

This electron micrograph of respiratory syncytial virus (RSV) illustrates five virions budding from an infected cell. The viral nucleic acid cores are obvious.

Type A Influenza virus

Ciliated cells are particularly vulnerable to injury and studies have shown that ciliated epithelial cells obtained from patients with culture documented viral upper respiratory infections exhibit transient changes in the microtubular organization of their airway cilia. Because optimal ciliary function is so closely attuned to ciliary organization, it follows that these defective cilia are limited in their capacity to clear the airways. The abnormalities of ciliary structure that appear in respiratory infections are distinctive from those characteristic of Primary Ciliary Dyskinesia (PCD) and although they may be commonly observed, they are less consistent and more focal in their distribution.

The figure below illustrates microtubular additions and deletions in cilia of a patient with a viral upper respiratory infection confirmed by culture. Note also that the central microtubules of two apparently normal cilia exhibit dysorientation similar to that seen in cilia of patients with PCD.

Microtubular additions and deletions in cilia

Bacteria

Bacteria are free-living prokaryotic (without a true nucleus) organisms which may parasitize the airway epithelium. Examples of respiratory diseases caused by bacteria are "whooping cough", "strep" throat, diphtheria, and otitis media. A variety of symptoms may accompany a bacterial respiratory infection including fever, sore throat, and cough. Antibiotics are an effective and appropriate treatment against bacterial infections. Some experimental studies have shown that infecting bacterial pathogens attach to the respiratory mucosa and in some cases is preferential for ciliated cells. The mechanisms whereby bacteria cause epithelial injury have not been not fully characterized although it appears that the organisms or their metabolic products may able to suppress ciliary activity and to cause the loss of ciliated cells from the airway lining thus impairing mucociliary clearance.

This is an electron micrograph of Group A Beta-streptococcus, the bacteria responsible for "strep throat."

Group A Beta-Streptococcus

This is an electron micrograph of Bordetella pertussis, the bacteria which causes "whooping cough."

Bordetella pertussis

Mycoplasmas

Mycoplasma pneumoniae is a respiratory pathogen which causes "walking pneumonia." The organisms shown in the scanning electron micrograph below are smaller than most bacteria, but larger than most viruses and; like bacteria, can live and reproduce outside the host cell. Infections caused by M. pneumoniae can be treated with antibiotics. M. pneumoniae is a highly contagious pathogen and often passes through settings where people are routinely in close contact such as day care centers, college dormitories, and military barracks. The organisms attach to host epithelial cells by a specialized tip structure which also is evident in the micrograph below. While the organisms apparently attach to and infect all epithelial cell types in the airways, they particularly impact on ciliary function, causing ciliary beat slowing and eventual cell death.

Mycoplasma pneumoniae

Air Pollution and Airway Health

There is a growing awareness in the scientific community of the relatedness of air pollutant exposure to adverse respiratory health effects. While air pollution concerns seem most often to be associated with industrialized settings and automobile use, some common air pollutants such as sulfur and nitrogen dioxide derive from combustion of fossil fuels and may be present in the home environment. Ultrafine particulates in the ambient air also may be a product of combustion and there is emerging data that these pollutants which are largely undefined chemically may impact adversely on respiratory health. while both particulate and gaseous pollutants may affect respiratory health, there is also growing evidence that some populations such as children and asthmatics may be particularly vulnerable to airway injury and the development of chronic respiratory diseases by exposure to polluted air.

The panel below illustrates a form of ciliary injury called compounding that is typical of injury by gaseous pollutants, particularly sulfur dioxide, a by-product of fossil fuel combustion. Here, the membranes of individual cilia have fused with one another to form large dysfunctional compound cilia.

Ciliary injury called, compounding

Insults such as this eventually result in loss of the entire ciliated cell from the epithelium and may lead to chronic bronchitis which may be characterized by mucus hyperplasia in which the ciliated cell population is replaced by secretory cells. This pattern is evident in the micrograph below.

Mucus hyperplasia

If the insult continues unabated, the epithelium may transition to a flattened layer known as squamous metaplasia seen below.

Squamous metaplasia

Evidence of squamous metaplasia in the airways is reflective of a serious chronic disease process and raises serious concerns for the development of even more adverse clinical outcomes including cancer. However, it is possible for the epithelial layer to revert from squamous metaplasia to its normal organization over time if the injurious stimulus is taken away. There is abundant research evidence that persistent injury of the epithelial layer can lead to neoplastic change from which the epithelium cannot recover. Further, the malignant cells may form a tumor requiring surgery and may metastasize and involve other organ systems. The image below is a histologic section from a bronchogenic carcinoma, a form of lung cancer.

Bronchogenic carcinoma

The Care and Maintenance of Good Respiratory Health

It has been said that one can live three weeks without food, three days without water, but only three minutes without air. Indeed, one if the major tenets of emergency medicine is to establish and maintain an airway. Those of us in good overall health tend to take our respiratory health for granted until we are challenged by infection or exposure to irritant fumes. There are some simple things we can do to promote good respiratory health.

  1. Don't Smoke or Use Tobacco Products. Don't start smoking. If you smoke now, STOP NOW! If you need motivation, take a good look at the images above. They could be you.
  2. Nutrition - There is a growing understanding in the research community of the importance of good nutrition in maintaining good respiratory health. There is good evidence that certain vitamin supplements and foods containing anti-oxidant compounds protect us from injury by certain pollutants.
  3. Avoid respiratory infection - This may seem easier said than done, but one simple and effective way to avoid colds and other acute respiratory infections is by hand washing. This is particularly true in environments where children are present. Secondly, it is possible to be immunized against some respiratory pathogens. Your doctor or pediatrician can explain the recommended schedule of immunizations to protect you and your child from contracting a respiratory illness due to certain viruses or bacteria. While we tend to think of our body's immune defenses as protecting us, there is an increasing awareness, that the inflammatory immune response to infection and subsequent injury may be detrimental to some extent and may contribute to the development of certain chronic respiratory disease states. Thus, while it is of paramount importance that we possess optimal immune function, it is best not to stress its limits with recurrent infection and injury.