BackgroundInflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress–induced pathology.ObjectiveWe sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells.MethodsMice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ.ResultsMice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β–induced ASM cell proliferation and CXCL8 release.ConclusionsMitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD.

Although ventilatory failure is the most common cause of death in amyotrophic lateral sclerosis (ALS) and measurement of respiratory muscle strength (RMS) has been shown to have prognostic value, no single test of strength can predict the presence of hypercapnia reliably. RMS was measured in 81 ALS patients to evaluate the relationship between tests of RMS and the presence of ventilatory failure, defined as a carbon dioxide tension > or = 6 kPa. We studied the predictive value of vital capacity (VC), static inspiratory and expiratory mouth pressures (MIP, MEP), maximal sniff oesophageal (sniff P(oes)), transdiaphragmatic (sniff P(di)) and nasal (SNP) pressure, cough gastric (cough P(gas)) pressure and transdiaphragmatic pressure after bilateral cervical magnetic phrenic nerve stimulation (CMS P(di)) to identify the risk of ventilatory failure in the whole group and in subgroups of patients with and without significant bulbar involvement. For patients without significant bulbar involvement, sniff P(di) had greatest predictive power [odds ratio (OR) 57] with specificity, sensitivity and positive and negative predictive values (PPV, NPV) of 87, 90, 74 and 95%, respectively Of the less invasive tests, per cent predicted SNP had greater overall predictive power (OR 25, specificity 85%, sensitivity 81%) than per cent predicted VC (9, 89%, 53%) and per cent predicted MIP (6, 83%, 55%). No test had significant predictive power for the presence of hypercapnia when used to measure RMS in a subgroup of patients with significant bulbar weakness. Thirty-five patients underwent polysomnography. CMS P(di), sniff P(di) and per cent predicted SNP were significantly correlated with the apnoea/hypopnoea index (AHI) (P = 0.035, 0.042 and 0.026, respectively). The correlations between AHI and per cent predicted MIP and VC were less strong (both non-significant). In ALS patients without significant bulbar involvement, novel tests of RMS have greater predictive power than conventional tests to predict hypercapnia. In particular, the non-invasive SNP is more sensitive than VC and MIP, suggesting that it could usefully be included in tests of respiratory muscle strength in ALS and will be helpful in assessing the risk of ventilatory failure. In patients with significant bulbar involvement, tests of respiratory muscle strength do not predict hypercapnia. Sleep-disordered breathing is correlated with RMS and the novel tests of RMS having the strongest relationship with the degree of sleep disturbance.

Romer LM, Polkey MI. Exercise-induced respiratory muscle fatigue: implications for performance. J Appl Physiol 104: 879 -888, 2008. First published December 20, 2007 doi:10.1152/japplphysiol.01157.2007.-It is commonly held that the respiratory system has ample capacity relative to the demand for maximal O 2 and CO2 transport in healthy humans exercising near sea level. However, this situation may not apply during heavy-intensity, sustained exercise where exercise may encroach on the capacity of the respiratory system. Nerve stimulation techniques have provided objective evidence that the diaphragm and abdominal muscles are susceptible to fatigue with heavy, sustained exercise. The fatigue appears to be due to elevated levels of respiratory muscle work combined with an increased competition for blood flow with limb locomotor muscles. When respiratory muscles are prefatigued using voluntary respiratory maneuvers, time to exhaustion during subsequent exercise is decreased. Partially unloading the respiratory muscles during heavy exercise using low-density gas mixtures or mechanical ventilation can prevent exercise-induced diaphragm fatigue and increase exercise time to exhaustion. Collectively, these findings suggest that respiratory muscle fatigue may be involved in limiting exercise tolerance or that other factors, including alterations in the sensation of dyspnea or mechanical load, may be important. The major consequence of respiratory muscle fatigue is an increased sympathetic vasoconstrictor outflow to working skeletal muscle through a respiratory muscle metaboreflex, thereby reducing limb blood flow and increasing the severity of exerciseinduced locomotor muscle fatigue. An increase in limb locomotor muscle fatigue may play a pivotal role in determining exercise tolerance through a direct effect on muscle force output and a feedback effect on effort perception, causing reduced motor output to the working limb muscles. respiratory muscles; exercise; diaphragm; abdominals; magnetic stimulation; metaboreflex THE PURPOSE OF THIS MINIREVIEW is to address the question of whether the respiratory demands of exercise contribute significantly toward exercise limitation, either directly through limitations of the respiratory muscle pump or indirectly through effects on limb blood flow and locomotor muscle fatigue. We describe the mechanical and metabolic costs of meeting the ventilatory requirements of exercise. We then ask whether the respiratory muscles fatigue with exercise, what factors contribute to any such fatigue, and what the implications of these factors are for exercise tolerance. Finally, we deal with the potential mechanisms by which respiratory muscle fatigue could compromise exercise tolerance and whether it is possible to overcome this potential respiratory limitation. Our review focuses on the healthy young adult exercising near sea level. However, we also consider special circumstances that determine the balance between metabolic demand and respiratory system capacity in the highly trained endurance ...

Background: Respiratory muscle weakness is an important clinical problem. Tests of varying complexity and invasiveness are available to assess respiratory muscle strength. The relative precision of different tests in the detection of weakness is less clear, as is the value of multiple tests. Methods: The respiratory muscle function tests of clinical referrals who had multiple tests assessed in our laboratories over a 6-year period were analysed. Thresholds for weakness for each test were determined from published and in-house laboratory data. The patients were divided into three groups: those who had all relevant measurements of global inspiratory muscle strength (group A, n = 182), those with full assessment of diaphragm strength (group B, n = 264) and those for whom expiratory muscle strength was fully evaluated (group C, n = 60). The diagnostic outcome of each inspiratory, diaphragm and expiratory muscle test, both singly and in combination, was studied and the impact of using more than one test to detect weakness was calculated. Results: The clinical referrals were primarily for the evaluation of neuromuscular diseases and dyspnoea of unknown cause. A low maximal inspiratory mouth pressure (PImax) was recorded in 40.1% of referrals in group A, while a low sniff nasal pressure (Sniff Pnasal) was recorded in 41.8% and a low sniff oesophageal pressure (Sniff Poes) in 37.9%. When assessing inspiratory strength with the combination of all three tests, 29.6% of patients had weakness. Using the two non-invasive tests (PImax and Sniff Pnasal) in combination, a similar result was obtained (low in 32.4%). Combining Sniff Pdi (low in 68.2%) and Twitch Pdi (low in 67.4%) reduced the diagnoses of patients with diaphragm weakness to 55.3% in group B. 38.3% of the patients in group C had expiratory muscle weakness as measured by maximum expiratory pressure (PEmax) compared with 36.7% when weakness was diagnosed by cough gastric pressure (Pgas), and 28.3% when assessed by Twitch T10. Combining all three expiratory muscle tests reduced the number of patients diagnosed as having expiratory muscle weakness to 16.7%. Conclusion: The use of single tests such as PImax, PEmax and other available individual tests of inspiratory, diaphragm and expiratory muscle strength tends to overdiagnose weakness. Combinations of tests increase diagnostic precision and, in the population studied, they reduced the diagnosis of inspiratory, specific diaphragm and expiratory muscle weakness by 19-56%. Measuring both PImax and Sniff Pnasal resulted in a relative reduction of 19.2% of patients falsely diagnosed with inspiratory muscle weakness. The addition of Twitch Pdi to Sniff Pdi increased diagnostic precision by a smaller amount (18.9%). Having multiple tests of respiratory muscle function available both increases diagnostic precision and makes assessment possible in a range of clinical circumstances.

There is no nonvolitional method of assessing quadriceps strength which both supramaximally activates the muscle and is acceptable to subjects. In 10 normal subjects and 10 patients with suspected muscle weakness we used magnetic stimulation of the femoral nerve to elicit an isometric twitch and measured twitch tension (TwQ), surface electromyogram in addition to the maximum voluntary contraction force (MVC). Supramaximality was achieved in all subjects at a mean of 83% of maximum stimulator output. When supramaximal, TwQ was reproducible (mean coefficient of variation 3.6%, range 0.7–10.9) and correlated well with MVC (r2 = 0.83, P < 0.001). In 7 normal subjects we measured TwQ before and after a fatiguing protocol; after 20 min TwQ was a mean of 55% (range 29–77%) of baseline and remained substantially reduced at 90 min. Magnetic femoral nerve stimulation is a painless, supramaximal method of assessing quadriceps strength and fatigue which is likely to be of value in clinical and physiological studies. © 1996 John Wiley & Sons, Inc.