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In humans breathing is an essential behaviour for life. It is recognized that humans and animals can perceive or sense their breathing, although the actual cortical and sub cortical structures by which this occurs remains unknown. The processing of sensations presumably arise from afferent information originating from mechanoreceptors within the muscles of the upper and lower airways, lungs and chest wall. This information is integrated by the central nervous system, which leads to a perception of respiratory sensations at th~ cortex, although the specific contnbutions of these sources remain unknown. In addition, distressing respiratory sensations such as breathlessness (dyspnoea) . and hyperinflation occur in individuals exhibiting pulmonary disease, such as asthma and chronic obstructive pulmonary disease (COPD). In response to these sensations, individuals can also voluntarily or behaviourally adjust their breathing. Hence, the aim of this thesis was to investigate: (i) the modulation of respiratory related sensory activity measured from the cortex in humans, using electroencephalography in response to applications of transient inspiratory occlusions (TIas) during hyperinflation, voluntary breathing and in tracheostomy patients' who lack an upper airway and (ii) the cortical and subcortical structures mediating the response to the TIO by using functional magnetic resonance imaging (fMRI). The results of these studies show that (i) voluntary breathing modulates respiratory perception, whereas perception is unaffected in tracheostomy patients and in hyperinflated states in response to TIas; and (ii) TIas can also generate cortical and sub cortical activity specifically activating sensory - motor structures including the, primary motor cortex, primary somatosensory cortex, supplementary motor area, inferior parietal areas, thalamus and cerebellum. In conclusion, respiratory perception (i) is altered by voluntary breathing; (ii) is unaffected .in hyperinflated and tracheostomized states; and (iii) can be investigated . using fMRl through the application of TIOs.

Injuries caused by explosions are an increasing threat. Primary blast lung injury, caused by the blast wave, precipitates intrapulmonary haemorrhage and subsequent oedema and inflammation. Treatment options are currently limited to supportive measures including mechanical ventilation. Recombinant activated factor VII (rFVIIa) promotes coagulation and reduces bleeding. It has been used to manage patients with traumatic bleeding that is not amenable to surgical haemorrhage control. Retrospective database analyses were undertaken to establish the epidemiology of blast lung injury in the military patient population, and the use of rFVIIa within military hospitals. These showed that the incidence of blast lung injury in those injured by explosion in the most recent conflict in Afghanistan is 11%. Use of intravenous rFVIIa in military hospitals is declining, due to a combination of factors including the introduction of bespoke targeted resuscitation, although rFVIIa may still have a role in the management of patients with haemorrhage not amenable to conventional treatments, such as blast lung injury. A programme of work was undertaken to develop an animal model of blast lung injury, in which a trial of nebulised rFVIIa could be undertaken. This involved the development of a reliable and reproducible model of blast lung injury in the rabbit, involving a shock tube. Work was also undertaken to establish that rFVIIa remained active after nebulisation, to define the distribution in the lungs following nebulisation, and to determine the amount deposited following nebulisation. Results showed that rFVIIa remains active following nebulisation, is widely distributed, and 10-15% is deposited in the lungs. The clinical problem of blast lung injury has therefore been defined in the population of interest, and the experimental work has established the methodology enabling a proof of principle study to be undertaken to determine whether rFVIIa, delivered by nebulisation, attenuates the haemorrhagic phase of blast lung injury.

The primary objective of this thesis was to examine the influence of alterations in muscle recruitment on pulmonary O2 uptake (VO2) kinetics during exercise above the gas exchange threshold (GET) in young people. In the first experimental chapter, the phase II time constant (τ) slowed over a 2-yr period in 14-16 yr old boys (25 ± 5 s vs. 30 ± 5 s, P = 0.002) and there was a greater relative VO2 slow component amplitude (Rel. A’2 (%)] during heavy-intensity exercise (9 ± 5% vs. 13 ± 4%, P = 0.036). In the second study, ‘work-to-work’ transitions yielded similar phase II VO2 kinetics during unloaded-to-moderate exercise (U→M) between 11-12 yr old boys and teenagers (19 ± 5 s vs. 22 ± 7 s, P = 0.32) but the phase II τ was significantly lengthened in the latter group at the onset of moderate-to-very heavy exercise (M→VH: 30 ± 5 s vs. 45 ± 11 s, P = 0.011). There were no differences in the phase II τ between teenagers and adult men during M→VH exercise (P = 0.46). In the third study, increasing pedal rate from 50 rev•min-1 to 115 rev•min-1 significantly (P < 0.01) lengthened the phase II τ (32 ± 5 s vs. 42 ± 11 s) and increased the relative VO2 slow component amplitude (10 ± 3% vs. 16 ± 5%) during VH cycling in untrained teenagers but the same parameters were unaltered by pedal cadence in trained junior cyclists (phase II τ: 26 ± 4 s vs. 22 ± 6 s, and Rel. A’2: 14 ± 5% vs. 17 ± 3 %, P > 0.05). The fourth study reported that a reduced relative VO2 slow component amplitude in younger boys compared to men (11 ± 4% vs. 16 ± 3%, P = 0.015) coincided with a lower percentage change in the integrated electromyogram (iEMG) of the m. vastus lateralis from minute 2 to minute 6 of exercise (ΔiEMG6-2: 7 ± 25% vs. 49 ± 48%, P = 0.030), suggesting that alterations in motor unit recruitment might be involved in restricting the O2 cost of exercise above the primary amplitude in children compared to adults. The final experimental chapter tested this hypothesis, but no statistically significant differences were reported for the relative VO2 slow component amplitude between 10-12 yr old boys and men (15 ± 7% vs. 19 ± 4%, P = 0.145). In boys, an excess VO2 temporally coincided with a significant increase in the transverse relaxation time (T2) of the m. vastus lateralis from the VO2 slow component time delay (SCtd) to minute 6 of exercise (41.5 ± 2.4 ms vs. 45.2 ± 2.3 ms, P = 0.001), thereby consistent with the notion that delayed muscle fibre activation might contribute to the development of the VO2 slow component in youth. In conclusion, this thesis has demonstrated that maturational changes in the VO2 kinetic response to heavy-intensity exercise are extended into adolescence. During intense submaximal exercise, the recruitment of higher-order (type II) muscle fibres might be principally involved in modulating VO2 kinetics as children mature but this effect is attenuated in teenage subjects engaged in regular endurance training.

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