Human tissues that are exposed directly to the outside environment include the skin, the gut, and the lungs. In all of these, unique cells must deal with the complexity of exposure to toxins and many kinds of microbes. As with the gut and the skin, the path of air into the lungs consists of many different environments that have microbe niches with different behavior and communications. Also like the gut and the skin, friendly microbes help contain others that might cause harm.

While the respiratory tracts are quite different from the other surfaces and deal with air borne material and gases, it is not surprising that similar vital conversations occur among lung lining cells, immune cells, and microbes as do in the other barriers of the gut, skin, and brain. This post will discuss the new research that is just emerging about these conversations along the entire respiratory tract. A future post will discuss the unique micro environments in the nose and mouth where vital conversations occur among many microbe species that are in some ways similar to those in the gut and in biofilms.

Most research showing elaborate communication among a wide variety of cells has been done in the gut, where a large number of metabolites of microbes have been discovered that are vital signals in digestion and in development of the specialized immune behavior. But, in the lungs, these interactions actually expand the roles in human health. It has been very difficult to perform this research until now because of the unique fragility of the air exchange mechanisms. 

Upper and Lower Respiratory Tracts

For this analysis of micro environments, there are basically two different anatomical regions—upper and lower respiratory tracts.

The upper respiratory tract includes the nose, sinuses around the nose, the region that connects the nose and pharynx, and the larynx region that is above the vocal cords. The lower includes the larynx below the vocal cords, the large trachea and then the airways that get smaller and smaller (bronchi and bronchiole), and then the smallest alveoli tufts where oxygen meets capillaries for gas exchange. The total surface area of the alveoli where exchange of oxygen and CO2 takes place is 40 times greater than the skin surface.

The upper respiratory tract has most of the microbes, but various microbes line all of the regions with specific species in niches. Microbes in the upper region are vital in avoiding infections from other invaders. Dangerous microbes must make a landing in the upper region and form a colony before they can potentially spread throughout the entire tracts.

If the first group of microbes in the upper respiratory tract can resist dangerous species, infections are avoided. As in the gut and skin, colonies of some species can be beneficial. Interactions with the lung cells are vital to these decisions. Conversations also determine the specific immune tissue development as in the gut and the skin. They even are related to the developing lung structure.

Air Borne Particles and Micro Environments

Ultimately the lung has many very complex gradients that are determined by the niche environments throughout the tracts. Factors include the amount of particles that are present, the pH, relative humidity, the pressure of oxygen and carbon dioxide, temperature, and density.

Only very small particles can reach all the way to the lungs, the larger ones being deposited in the upper tracts, such as bacteria and viruses. The density of microbes is measured in different ways at different regions, from air measurements, to nasal swabs to estimates from oral washes.

The number of particles gradually goes down from outside to inside, as the pH increases. Humidity and temperature change most in the nose. Oxygen and carbon dioxide have opposite gradients. The surface area stays mostly the same until the trachea and then vastly increases.

Development of Respiratory Tracts

From the fourth week of the fetus, the upper respiratory tract is quite different than the final outcome. There is a much larger nasopharynx and smaller oropharynx—the larynx is higher. The early lung has no alveoli. Alveoli start late in the fetus and grow for three years after birth. The many niche compartments evolve even up to adulthood.

The introduction of microbes appears to be necessary and germ free mice have smaller lungs and less alveoli. The special immune tissues (nasopharygeal associated lymph tissue or NALT) starts after birth requiring microbes for development as in the skin and gut.

It is not really known whether fetuses have microbes or not, but antibodies and particles from mother’s microbes are definitely present (see post on maternal immune system influence on brain development). This exposure affects the newborn’s response to the sudden onslaught of many microbes, at first from the mother.

Healthy babies upper respiratory tracts at first have many Staph, Corynebacterium, and Dolosigranulum. Later, it becomes mostly Moraxella at 6 months. These are influenced by feeding and type of birth. Vaginal and breast fed seem to help this transition. Breast milk has more antibodies and the positive Bifidobacterium and Lactobacillus. Antibiotics can alter these with less of these healthy varieties. The many environmental factors have a big influence such as season, vaccinations, siblings, and smoke exposure. By age three, the adult types occur. Smoking affects microbes in the upper, but not definitely in the lower tract. The timing of exposure determines activity later.

The upper tract is the guardian and barrier for the rest. Each region has different structural lining cells in each niche for different exposures. Each also has unique fungus, bacteria and viruses. The part of the nose closest to the outside world has skin like epithelial cells with keratin (see post on skin). In this first region there are several kinds of glands producing serous material and sebum that defines fat eating microbes.

Deeper in the nose cavity is the nasopharynx. This has several kinds of lining epithelial cells, some stratified squamous and some special respiratory cells. There are more types of microbes including Haemophilus, and Strep. Even more diverse microbes are in the oropharynx with stratified epithelial lining without keratin.

There is high presence of viruses including rhinovirus HRV, adeno, corona, boca and polyoma viruses. There are many others recently discovered with the most common being Anelloviridae. This region has fungus including Aspergillus, Penicillium, Candida, and Alternaria. In gut, fungus are 0.1% of microbes and skin 3.9%. It is not known the percentage in the lungs.

In other organs a more diverse microbe set has been associated with health, such as less inflammatory bowel disease, infections, and obesity. This is true in the vagina as well. In upper respiratory tract, ear and sinus infections are associated with less diversity. But, it appears to be different with each specific niche. The upper respiratory tract is a large source of infections.

There are some specific species that are very beneficial (called keystone species) including Dolosigranulum and Corynebacterium that keep dangerous bugs out, such as Strep causing pneumonia. The local species use all nutrients as one tactic to avoid other colonies.

Research shows that in the nose Staph epidermidis stopped the more dangerous aureus. They also make enzymes that eat up biofilms (by serine protease). They talk with neutrophils that then are more able to kill pneumoniae after conversing with Haemophilus influenza.

Lung Cells and Microbes

The large airways of the lungs have similar epithelial lining cells as the upper tract. They gradually change in shape deeper in the lung to become more cube. The epithelial lining cells in the alveoli are unique.

Up until recently the lower tract was not considered to have many microbes at all. But, recently a large number were found with new techniques. The density has been too low for previous techniques such as 1000 per ml^-1. It is very hard to get samples from deep in the lungs. Also, the amount of DNA is so low that it could be contamination. This sampling is most difficult in infants when not already intubated.

Small droplets can travel from the upper to the lower and microbes can separate and scatter from the lining and mucous. The oropharynx seems to send most of the microbes to the deep lung tracts in healthy people. In children they can come from the nose with more secretions being produced.

Preemies have mostly Staph, Ureaplasma and Acinetobacter. Young children are the same as the upper tract with Moraxella, Haemophilus, Staph and Strep.

Adults have Firmicutes including Strep, Veillonella, and Bacteroidetes. Tropheryma whipplei is only deep in the lungs and not elsewhere in the tracts. For viruses, phages are very common and often Anelloviridae. Healthy lungs have the fungus Eremothecium, Systenostrema, and Malassezia.

There doesn’t seem to be specific special niches deep in the lungs. This implies that microbes in the lung are transient and mostly from the upper tract, not specific resident communities. Still, these microbes traveling through somehow affect development of immune function through conversations.

Friendly and Unfriendly Microbe Conversations

Positive and negative relationships among microbes are just now being studied in the lungs. A number of posts have discussed these relationships in the gut, where there is much more known already. One group of oropharyngeal microbes that have positive effects are Veillonella. They have community signaling that build specific Strep biofilms that are beneficial. These conversations keep away dangerous Strep and nasopharyngeal Moraxella and H influenza. Also, communication is vital between Corynebacterium and Staph. There are many species and strains involved in these multiple interactions.

Corynebacterium and S. aureus induce each other to increase through signals. Other signals are antagonistic with S. aureus against pneumoniae. This signal can be pneumoniae producing hydrogen peroxide which produces larger numbers of phage viruses that attack aureus. The species Neisseria lactamica will stop meningitides avoiding dangerous meningitis.

Some microbes produce a large amount of products and these microbes train the infant immune system to respond. For example, S. aureus is very prominent in infants without causing disease. When Corynebacterium striatum signals to aureus, it causes it to not become dangerous. Staph types also stop aureus from becoming dangerous, such as epidermidis making enzymes to stop them. Another Staph (lugdunesis) makes a specific factor that kills dangerous bacteria.

Microbes Indirectly Affect Other Species.

Bacteroidetes stop lung inflammation, by communicating with cytokines and affecting neutrophils. Products stimulate release of peptides against other microbes from the immune cells. The helper T cells Th17 are part of these conversations and were first stimulated by other microbes.

Signals from upper tracts stimulate lower tract cells in the lungs. These stopped inflammation from flu virus. Lactobacillus in the nose stopped lung infection of pneumovirus.

Immune cells in the gut also affect respiratory inflammation. Conversations of gut T cells and dendritic cells stop lung microbes from attacking the epithelium and cause more regulatory T cells. Specific lung bacteria stopped inflammation through Th17 and macrophages. More Proteobacteria affected inflammation in alveoli.

Several microbes affect the amount of free fatty acids that alter growth of specific species. Dolosigranulum increases acidity which helps Corynebacterium. But, they also have direct signals as well. There are many other interactions that are just now being discovered and the picture is not yet clear.

Virus and Bacteria Conversations in the Respiratory Tract

In 1919 millions died from bacterial pneumonia after first getting flu virus. Viruses appear to disrupt the barrier between the airway and the lining cell. This allows dangerous bacteria to grab onto the site. Flu virus stimulates molecules from the lining cells that feed bacteria. They also slow down the cleaning apparatus of the cilia. Viruses trick the immune responses as well making it easier for bacteria. One way is by altering white blood cells (monocytes) and changing the responses of scavenger macrophages in the alveoli. They also can stop specific peptides from Th17 cells that would kill bacteria.

Bacteria increase viruses by stimulating adhesion receptors for viruses to grab onto lining cells. They also increase inflammation response causing more infection. Some bacteria stop specific viruses directly or by affecting immune cells. The molecule lipopolysaccharide LPS (which is from gram neg bacteria) is a necessary signal for immune conversations and future responses to viruses. Also, phages are everywhere stimulating the antiviral defense systems (CRISPR) in bacteria.

Fungus Conversations with Bacteria

There is only rudimentary knowledge of this important interface in the lungs because of the difficulty in tracking these interactions. But, biofilms from multiple bacteria cause enough problems for the lung lining epithelial cells to form fungus biofilms (aureus, Strep, and aeruginosa). Some of these bacteria form products that are volatile and these stimulate aspergillus at a distance.

The opposite happens when the fungus candida sends signals that increase aeruginosa by first affecting reactive oxygen from macrophages in the alveoli. Therefore, the conversations including fungus are involved in maintaining health in the lungs.

Lung Conversations with Microbes

Inflammation can have a dramatic effect on the necessary exchange of gases. Just as the skin and gut are exposed to factors from the environment, the lungs have the most exposure to particles in the air. Mucus is vital to control these particles. Microbes are captured in this mucous in the nose and then moved up and out by beating of cilia along the lining cells. Special molecules such as glycoproteins stimulate cytokines and macrophages that work against inflammation and clean debris.

Mucous, also, includes immune globulins that cover receptors on the lining cells not allowing dangerous microbes to attach. A special mixture of fats and proteins help maintain the shape and function of the delicate alveoli by reducing surface tension. These surfactants affect the surface tension and fight inflammation and dangerous microbes. These molecules stimulate macrophages to eat debris.

The lung epithelial cell maintains the barrier from microbes including the underlying wall made of connective tissue called the lamina propria. This layer is dynamic and produces molecules that fight microbes as well (beta-defensin 2). These epithelial cells and the immune cells have receptors that sense particular microbes from fragments and responds. Special cells in micro folds carry bacteria and particles to the lamina propria below to meet dendritic cells to stimulate more immune response. These dendritic cells live just under the alveoli lining epithelial cells and they sample the alveoli space, just as they stick out their hands in the gut into the lumen to capture microbe particles. These cells present to T cells in lymph nodes that drain from the lungs.

Macrophages can exist in different forms and the type that works against inflammation is part of the conversations of the lining cells, dendritic cells, and T cells.

There are many examples of how respiratory microbes are needed in a window of time to allow children to develop its immune system. The specialized lung immune tissue is stimulated with bacteria toxins. LPS from bacteria cause the particular forms of immune lymphoid tissues in the bronchus. Bacteria in infants, not adults bring regulatory T cells to the skin helping good microbes to attach. Lung microbes cause alterations in T cells responses. Cytokines are necessary for natural killer T cells related to asthma.

Lasting viral infections are involved in producing and regulating immune responses both for adaptive and innate immunity. There are a huge number of viruses changing each day in the blood, including 10 billion anellovirus. This causes immune cells to constantly observe these viruses and their activities. Herpes virus exists in 90% of people and have evolved in mammals for millions of years. They stimulate cytokines producing macrophages. Also, common respiratory viruses stimulate immune responses that continue afterward such as more natural killer T cells. They produce excessive reactivity in the lungs. Another virus (syncytial RSV) alters T cells causing more reactive airways.

Vital Conversations Among Cells in the Lungs

It is much harder to observe cellular conversations in the respiratory tract than in the gut and on the skin. One reason is that the lung is constantly responding to air borne particles and have many different factors affecting micro environments of lining cells. These factors include moisture, pH, density of air particles, mucous, and pressures of oxygen and carbon dioxide. As in the gut, there are many different microenvironments based on these differences. And like in the gut, conversations among a variety of cells, including lining epithelial cells, immune cells, and microbes determine friendly and unfriendly resident microbes and the development of specialized immune tissue.

For years it was thought that there were no microbes in the lungs normally. Now it is known that there are at least transient airborne microbes and some resident species. These somehow determine immunity in the lungs. It is more difficult to study microbes and cells in the lungs than in the gut, because of the delicate nature of air exchange in the alveoli and other factors.

It has been discovered already that the same types of interactions occur among microbe species that determine which become dangerous. As research continues, the vital conversations will be found and new treatments for lung disease.