## 3 Air Pollution Induces a Stress Response and Disrupts the PINE Network
### Pro-Inflammatory Response  
Inhaled PM triggers pulmonary protein leakage and inflammation in a size-, dose- and solubility-dependent manner [58; 59]. The persistence of inhaled particulates may prolong these effects. Exposure to PM influences multiple organ systems indirectly via the production of inflammatory factors and triggering of nervous reflexes, and directly via access to the circulation where they disrupt cellular, tissue and organ function to modulate autonomic nervous system (ANS) activity [60; 61; 62; 63]. The impact of PM on pro-inflammatory responses are associated with the size of the particles. Due to their size, PM10 are restricted to the pulmonary system, where they locally increase reactive oxygen species (ROS) and inflammatory cytokines [64]. PM2.5 are associated with elevated inflammation and oxidative stress, together with changes to ANS activity [10]. Exposure to PM2.5 elevates inflammatory markers including CRP, TNF-\(\alpha\), PGE2 and II-1\(\alpha\) together with ET-1 [65; 66]. PM0.1 are also heavily implicated in airway diseases, but have also been shown to be associated with inflammation in the cardiovascular and central nervous system [11] ([PERSON] et al., 2012). Chronic inflammation is linked to proximity to roadways, where there are increased PM levels [67]. Inhalation of poorly soluble pollutants such as ozone, NO\({}_{2}\) and phospene also induces pulmonary inflammation [68; 69], with changes focused within the lower respiratory tract [70; 71]. Conversely, water soluble sulphur dioxide, chlorine and ammonia may predominantly influence the nasopharynx [72; 73; 74; 70]. Volatile organic chemicals in vehicle and other pollutant sources are also detrimental to cardiovascular health [75], and lead to immunosuppression [76] and Alzheimer's disease [77]. For example, acute acrolein exposure induces dyslipidaemia [78] and vascular dysfunction [79; 80], while chronic exposure promotes atherosclerosis and lesion rupture [80; 81] and impairs protective anti-infarct signalling [82]. Microparticulate exposure additionally triggers adipose tissue production/release of cytokines, contributing to systemic inflammation and hepatic insulin-resistance [71]. There is also evidence of immune cell mobilisation from bone marrow in response to PM exposure [83; 84; 85]. Despite these clear pro-inflammatory changes, mixed effects of air pollution on circulating cytokines are still reported, ranging from increases in humans and animals [86; 87; 88] to no apparent change [89; 90; 91]. These different peripheral changes and inflammatory processes contribute to a neurogenic inflammation with air pollution exposure [92; 93]. Activation of neuronal and epithelial transient receptor potential proteins (TRPs) by pollutant products triggers a tachykinin (e.g., substance P, neurokinin A) release [94; 95; 96], whilst capsaicin-sensitive TRPV channels evoke a neuronal tachykinin release [97], and ion channel receptors trigger a neuronal neurokinin release [98; 99]. This induces neurokinin-receptor-dependent pulmonary inflammation [100; 101], with pulmonary injury and cytokine production spilling over into the systemic circulation, contributing to metabolic changes and propagating vascular and CNS inflammation [102; 103]. Neuroinflammation, in turn, contributes to mental health issues such as MDD and other NCDs via perturbation of the PINE network [3; 5]. Inflammatory mediators produced with pollutant exposure may activate glial cells in the CNS [104]. Interestingly, cytokine-mediated NF\(\kappa\)B signalling in the hypothalamus appears to enhance particulate-induced systemic inflammation and metabolic changes [71], supporting positive feedback augmentation of inflammation via the CNS. Central stress-axis regions such as the paraventricular nucleus (PVN) of the hypothalamus may also be activated via sensory irritant activation of the trigeminal and vagal nerves with pulmonary oxidative stress/irritants, stimulating sympathetic and HPA-axis activities and hormone release.