**2. Saliva and salivary glands: pre-, during- and post-RT**

Briefly, exocrine salivary glands are classified as either major (parotid, submandibular and sub-lingual) or minor (labial and buccal gland, glosso-palatine gland, and palatine and lingual) glands. Anatomically, all three major glands are highly vascularized, innervated and are architecturally similar featuring a ductal structure with a secretory/excretory (saliva-producing acini surrounded by myo-epithelial cells, myo-fibroblasts, immune cells, stromal cells, endothelial cells and nerve fibers) opening into the oral cavity/mouth [15]. The glands differ in their type of acinar cells and as a result, in the type of produced saliva. While the parotid is composed of only serous acini thereby producing watery saliva, the sub-mandibular and sub-lingual glands contain a mix of serous and mucous (glycoprotein- rich) acini, thereby producing saliva of a different composition, a seromucous secretion. Secretion of saliva is stimulated by the sympathetic (proteins) and parasympathetic (serous/ions) branches of the autonomic nervous system [15, 16].

Saliva is basically an oral lubricant fluid with multiple digestive functions critical for oro-dental health, QoL and general well-being. It is composed of a complex mixture of water (99%), electrolytes (sodium, potassium, calcium, magnesium, etc. …), mucins, proteins, white blood cells, epithelial cells, immunoglobulins, anti-microbials/−bacterials and enzymes (1%) [16–18]. Hence, saliva is essential for moistening, chewing, swallowing and chemically-digesting foods. It also facilitates speaking, aids the tongue in taste sensing, helps protect the oral mucosa (localized immunity/mucosal resistance) and plays a role in tissue re-mineralization. A healthy adult produces/secretes a daily average of 0.5–1.5 L, at differential rates over the day, and at a near neutral (buffer) pH of 6.7 [15–17, 19–22].

Therefore, alterations in quantity (↓: hypo- or ↑: hyper-salivation) or quality of the secreted/produced saliva are associated to a variety of conditions and diseases

and have been associated with some medications and therapies [23]. For instance, sialorrhea is a general term used for hyper-salivation (or drooling), often as a result of medication, systemic diseases, psychiatric disorders and/or oral pathologies, amongst others [14]. It is also often linked to conditions such as Parkinson's, epilepsy, amyotrophic lateral sclerosis or ALS, cerebral palsy, developmental disabilities, pregnancy and/or drugs including clozapine [16, 24] Common treatments for sialorrhea include surgical intervention, radiation of the salivary glands (to halt and diminish its function) and the use of oral anti-cholinergic drugs (to inhibit saliva production), however with known side or adverse effects. In recent years, numerous studies investigated the use of neuro-toxins, mainly botulinum neurotoxins or BoNTs, which basically are bacterial exotoxins that interfere and block the exocytotic release of vesicular neuro-transmitters cholinergic neuromuscular activity in the target tissue, including commercially-available RimabotulinumtoxinB (RimaBoNT-B, FDA approval in 2000) and IncobotulinumtoxinA (IncoBoNT-A, FDA approval in 2010) in patients suffering sialorrhea, with attractively promising results [24, 25].

On the other hand, salivary gland hypofunction (*progressive* loss of gland function) is commonly described or associated with the reduction of salivary flow and production, quantitatively. Frydrych [26], discussed salivary gland hypofunction etiology and classified causes into seven major areas, developmental, autoimmune/chronic inflammatory, endocrine, neurological/psychiatric, metabolic, infectious and iatrogenic [26]. In a healthy individual, un-stimulated "whole" salivary flow rate is averaged at 0.35 mL saliva per minute, with abnormalities indicated if the rate drops. For example, one of the most prevalent and studied diseases or disorders of the salivary gland is Sjögren's syndrome (SS), a chronic auto-immune inflammatory reaction characterized by lymphocytic infiltration of the exocrine glands (mostly to the salivary or lacrimal glands), which generates a significant reduction in salivary flow rate - to below 0.1 mL whole saliva per minute secreted, un-stimulated [27]. It is perhaps noteworthy herein that *whole* saliva indicates the collection of saliva (secreted from all salivary glands) present in the mouth. Other quantification techniques require direct collection from the specific gland. Moreover, often is reported in diagnosing SS that only un-stimulated whole saliva flow rates are used.

Hypo-salivation, therefore, is salivary flow rate reduction, quantified, clinically via sialometry. Xerostomia, on the other hand, is the reported perception or sensation, subjectively, of oral dryness. Hypo-salivation may or may not be accompanied by xerostomia, and vice versa. Dryness in the mouth can be a side-effect of medications or due to diseases such as HIV/AIDS, diabetes, hypertension and/or other factors including smoking, dehydration, mouth breathing, aging and/or head and neck irradiation [14, 16, 23, 28, 29]. Indeed, xerostomia is one of the most commonly reported (and expected) complications of RT (during and after RT) for HNC, and as mentioned earlier, mainly as a predictable consequence to the significant damage (and generated inflammatory immune response) caused to the salivary glands which are located and included within the RT-zone or field [30–32].

RT, besides impairing salivary gland function and salivary flow rate, impacts the quality of the secreted saliva, given the loss or atrophy of acinar and ductal cells and granules (and stem/stromal and progenitor cells) and the consequential morphological changes to salivary fluid quality (including pH and buffering capacity), thereby affecting the essential protective, functional and overall physiologic processes (**Figure 2**). Such damage [32] and impact can appear as soon as one week after the first radiation therapy session (*acute RT-induced damage is due to a disturbance in the involved signal transduction pathways on the cell membrane*). Progressive

*Salivary Gland Radio-Protection, Regeneration and Repair: Innovative Strategies DOI: http://dx.doi.org/10.5772/intechopen.94898*

#### **Figure 2.**

*Progression of RT-induced salivary gland damage and dysfunction in HNC patients.*

decrease in salivary gland function is evident with more RT sessions (*delayed or late RT-induced damage is due to apoptosis-driven parenchymal cell loss, inflammation, blood vessel dilation and function loss, nerve injury and reduced parasympathetic nervous function, and fibrosis)* rendering rescue, repair and regeneration rather challenging [33–35].

As a result, the QoL of a large proportion of patients receiving RT is severely compromised [36, 37], with thicker or more viscous saliva and xerostomia leading in reported complaints [38]. Indeed, RT-related biochemical and proteomic alterations where several key glycoproteins, proteins and other molecules are affected have been identified [31, 39]. For example, Jehmlich *et al.* [40], discussed such variations post-RT, detected significant alterations in 48 proteins and highlighted the development of oral mucositis as a result of salivary gland dysfunction. Psychosocial and emotional impact on QoL of HNC patients, especially the elderly [41], where they experience and suffer from a compromised ability to and taste, chew, and swallow foods extended to their forced switching of dietary preferences to soft and carbohydrate-rich foods, thereby resulting in serious nutritional deficiencies [38, 40, 41]. Hyposalivation and sequential xerostomia also affect speaking and communication abilities, and patients experience nocturnal oral discomfort, hence, causing additional stress leading to withdrawal from everyday or day-to-day societal and emotional interactions [42–44].

Furthermore, with the prolonged oral clearance of sugars, the oral mucosa becomes painfully-dry, sticky and more susceptible to infection, the progression of dental caries (tooth decay), gingival and periodontal disease and trauma, accentuating the importance of oro-dental hygiene and care, especially in the elderly patients [41]. Other sequelae include erosion and ulceration of mucosal tissues, oral candidiasis, dysgeusia and dysphagia. Therefore, it is common for HNC patients to suffer from depression, feelings of anguish and anxiety after receipt of the RT protocol [14, 37, 45–49]. While the recovery of irradiated salivary glands at the cellular and molecular has been thus far shown to be limited, salivary recovery post-RT, from our clinical exposure and expertise, is possible, yet a lengthy (> 3 years), dire and capricious process, with underlying mechanisms not yet fully understood.
