## 3 Lipid Peroxidation  
To understand the random mixture of aldehydes that is formed under LPO conditions, consider the representative reactions of the \(\omega\)-6 fatty acids linoleic and eicosadienoic, **1a** and **1b**, respectively (Figure 2). While 2-5% of major pulmonary phospholipids are linoleic [23], eicosadienoic is not as prevalent but still common [24]. For reasons related to free radical stability [25], hydrogen atom abstraction by ROS generated under oxidative stress predominantly occurs at the bis-allylic methylene position to produce the doubly resonance-stabilized free radical **2**. Resonance delocalization leads to the scrambling of alkene stereochemistry to afford isomeric mixtures of \(E\) and \(Z\) alkenes at carbons 9-12 for **2a** and carbons 11-14 for **2b**. The subsequent reaction with molecular oxygen generates peroxyl radicals, which afford corresponding pentadienylic hydroperoxides, such as **3a,b** and **5a,b**, as well as bis-allylic hydroperoxides [26], such as **4a,b**, on hydrogen atom transfer from resident hydrogen donors that include neighboring PUFAs [27], resulting in the propagation of the free radical-mediated process. The peroxyl radicals derived from PUFAs with high degrees of unsaturation often undergo cyclization reactions to generate cyclic peroxides [28], leading to complex mixtures on subsequent cleavage [29]. Redox active metals, such as Fe(II) [30], V(IV) or V(V) [31], and Cu(I) [32], deplete hydroperoxides by generating alkoxy radicals [33; 34; 35] that undergo carbon-carbon bond scission to release corresponding aldehyde and alkyl radical products [36]. Conversely, hydroperoxide activation via enzyme-mediated (e.g., phospholipid hydroperoxide glutathione peroxidase (phGPx) [37; 38], cytochromes P450 (CYP2S1, CYP3A4) [39] or acid-induced processes actuate Hock-Criege rearrangements [40; 41]--peroxide O-O cleavage via neighboring group 1,2-migration--to deliver the mixture of hemicacticals **6-9**. Each hemicactical dissociates to two aldehydes, with the lipid tail-derived fragments (in red, Figure 1) producing the more volatile aldehyde fraction consisting of hexanal, heptanal, 2-octenal, and 2-nonenal. In the case of nonenal, the unsaturated aldehyde may be formed with \(\beta\),\(\gamma\)-unsaturated that subsequently undergoes isomerization to the thermodynamically preferred \(\alpha\),\(\beta\)-position or react with ROS to produce hydroxylated products (e.g., 4-hydroxy-2-nonenal, 4-HNE), as discussed next [22]. In addition to aldehydes derived from lipid mono-peroxidation, bis-peroxidation processes also contribute to diversify the mixture of volatile aldehydes generated under LPO conditions [22]. As examples, a reduction in lipid hydroperoxides **3a,b** delivers dienyl alcohols **10a,b** that undergo subsequent radical-mediated reactions with diatomic oxygen at various positions to afford hydroperoxides **11a,b** and **14a,b** after hydrogen atom transfers (Figure 3). These adducts then are transformed as noted above via hemiacetals **12a,b** and **15a,b** into the hydroxylablehyde products 4-hydroxynonenal (4-HNE) and 2-hydroxyheptanal, respectively. Peroxyl radical additions to dienyl intermediates, such as **10a,b**, also occur to generate new radical species that can react with oxygen, as exemplified by the formation of **13a,b**. The subsequent fragmentation [42] of the 1,2-bishydroperoxides produces 4-HNE. As shown in Figure 3, a principal 2-hydroxyaldehyde formed under oxidative stress is 2-hydroxyheptanal [43; 44]. Whereas short-chain 2-hydroxyaldehydes are known as products of lipid peroxidation [43; 45], detecting them in exhaled breath presents a considerable challenge due to their facile dimerization, a consequence of the higher carbonyl reactivity imparted by the inductive effect of the adjacent C-OH group [46].