While the respiratory tract is usually seen to be in a “low state of alert” vis-à-vis the plethora of aerogenic stimuli (Holt et al. 2008), responding to an infectious organism brings with it the need to do this in a measured and balanced way, in order that the host may regain its steady state integrity, minimizing so-called bystander damage. This is a dual edged sword that the host is wielding and is exemplified by molecules like nitric oxide, which, on the one hand, is part of the respiratory tract’s arsenal to respond to infectious organisms, which on the other hand, under excessive production and conversion to reactive metabolites can lead to tissue damage of the host (van der Vliet et al. 2000). Any stress-related tipping of this fine balance can lead to potentially deleterious local over-inflammation.

At the mucosal interface between host and microorganism, adhesion of bacteria to respiratory epithelial cells is influenced by very different stress-associated factors: bacterial adhesion is improved through expression of proteins that are induced by the paucity of iron which is effected by the host as a means of protection against iron-requiring pathogens (Perez Vidakovics et al. 2007). To the possible detriment of the host, bacterial binding to respiratory epithelia also tends to occur with greater efficiency in the hypersecretory conditions of inflamed airways, when the decoration of mucin glycoconjugates is altered (Davril et al. 1999).

Those microorganisms able to form biofilms are more likely to possess the ability to translocate the respiratory epithelial cell layer into deeper tissues than those that have lesser cohesive and adhesive organization (Yamazakki et al. 2006), and they thereby mediate the progression from inflammation to infection. It is therefore of interest that several of the immune effectors released during stress, particularly the catecholamines norepinephrine, epinephrine and dopamine, can induce changes in the bacterial phenotype relevant to biofilm formation such as adhesion to host epithelia (Vlisidou et al. 2004). In terms of the respiratory tract, catecholamines are naturally present in secretions due the role they play in regulating respiratory function (Table 10.1).

All patient groups share an increased risk of respiratory infection while in hospital; those in intensive care units receiving ventilation are at particular risk of developing so-called ventilation-associated pneumonia (Fridkin 1997). It is known that intubation/long dwelling catheters are associated with biofilm formation and sepsis from bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa (Fridkin 1997). Interestingly, such bacteria have been shown to be receptive to the stress hormones that are elevated in acutely ill patients (Freestone et al. 2008a). What is also of significance is that patients in intensive care are frequently prescribed catecholamine inotropes, drugs that have been shown to increase commensal bacteria biofilm production in intravascular catheters (Lyte et al. 2003), as well as resuscitation of antibiotic-damaged pathogenic bacteria (Freestone et al. 2008b).

How might the catecholamines that are released into the respiratory mucosa during acute stress, or applied therapeutically, influence the infectivity of any potentially pathogenic bacteria within the vicinity of the elaborated hormone? The first context is growth. All pathogenic bacteria require iron to grow in vivo. This growth is prevented due to the presence of lactoferrin and transferrin, key innate immune defense proteins the role of which is to bind all free ferric iron, thereby making blood and respiratory secretions too low in iron to support the growth of iron-requiring pathogens. To overcome this usually very effective iron-limitation defense of host fluids, bacteria produce siderophores, very high affinity secreted ferric iron binding molecules, which allow them to acquire the transferrin and lactoferrin-sequestered iron. Work from several groups has shown that catecholamine stress hormones can also function as direct bacterial siderophores (Freestone et al. 2000, 2002) (see also Chap.​ 3 ). This stress hormone provision of iron can induce up to a million fold increase in the growth of pathogenic bacteria, including those causing airway infections such as Klebsiella pneumoniae and Pseudomonas aeruginosa and Bordetella species (Freestone et al. 1999; Alverdy et al. 2000; Anderson and Armstrong 2006, 2008). Epinephrine, norepinephrine, dopamine, and their metabolites can all reduce the iron-limiting function of bacteriostatic, key innate defense, proteins lactoferrin, and transferrin (Freestone et al. 2002). Through interaction of these host iron-binding proteins with stress hormones, blood and epithelial secretions are rendered much less bacteriostatic as bacteria are able to access normally inaccessible host sequestered iron sources (Alverdy et al. 2000; Freestone et al. 2000, 2002, 2008a; Anderson and Armstrong 2006, 2008). Bordetella species, significant respiratory pathogens of infants (causing whooping cough), also make use of stress hormones to increase transcription of several iron acquisition components (Anderson and Armstrong 2006, 2008). Dopamine, norepinephrine, and epinephrine are all able to induce the transcription of bfeA, the gene for the Bordetella enterobactin/catechol xenosiderophore receptor. In addition, as has been shown for many enteric and skin bacteria (Freestone et al. 1999), norepinephrine also stimulate growth of Bordetella bronchiseptica growth in iron-limiting medium containing serum, via enabling the bacteria to access transferrin bound iron (Anderson and Armstrong 2006, 2008). As already noted, respiratory secretions are markedly iron limited, though the action of host iron binding proteins, and catecholamines may therefore represent a route by which respiratory pathogens, such as B. bronchiseptica, could obtain essential iron in the host environment (Anderson and Armstrong 2006, 2008). Exposure of respiratory pathogens to stress-released hormones can also induce the bacteria to synthesize their own growth factors, the mechanism of action of which is non-transferrin dependent (Freestone et al. 1999). Thus, the effects of stress hormone exposure on bacteria can be manifest long after the initial stress event has ended, and catecholamine levels returned to normal.