Gaspar A. Farkas

Diaphragm structure and function in health and disease.

The diaphragm is the primary muscle of inspiration, and as such uncompromised function is essential to support the ventilatory and gas exchange demands associated with physical activity. The normal healthy diaphragm may fatigue during intense exercise, and diaphragm function is compromised with aging and obesity. However, more insidiously, respiratory diseases such as emphysema mechanically disadvantage the diaphragm, sometimes leading to muscle failure and death. Based on metabolic considerations, recent evidence suggests that specific regions of the diaphragm may be or may become more susceptible to failure than others. This paper reviews the regional differences in mechanical and metabolic activity within the diaphragm and how such heterogeneities might influence diaphragm function in health and disease. Our objective is to address five principal areas: 1) Regional diaphragm structure and mechanics (GAF). 2) Regional differences in blood flow within the diaphragm (WLS). 3) Structural and functional interrelationships within the diaphragm microcirculation (DCP). 4) Nitric oxide and its vasoactive and contractile influences within the diaphragm (MBR). 5) Metabolic and contractile protein plasticity in the diaphragm (SKP). These topics have been incorporated into three discrete sections: Functional Anatomy and Morphology, Physiology, and Plasticity in Health and Disease. Where pertinent, limitations in our understanding of diaphragm function are addressed along with potential avenues for future research.

Ventilatory dysfunction in mdx mice: Impact of tumor necrosis factor–alpha deletion

Muscular dystrophy is associated with inflammation and fiber necrosis in the diaphragm that may alter ventilatory function. The purpose of this study was to determine to what extent in vivo ventilatory function in dystrophic (mdx) mice was compromised and to assess the impact of deletion of tumor necrosis factor–alpha (TNF‐α), a known proinflammatory cytokine, on ventilatory function, diaphragm contractility, and myosin heavy chain (MHC) distribution in 10–12‐month‐old mdx mice. Although the resting ventilatory pattern did not significantly differ between control and mdx mice, the ventilatory response to hypercapnia in mdx mice was significantly attenuated. Elimination of TNF‐α significantly improved the hypercapnic ventilatory response and diaphragm muscle maximal isometric force. Long‐term TNF‐α deletion also altered the myosin heavy chain isoform profile of the diaphragm. These data indicate that a blunted ventilatory response to hypercapnia exists in mdx mice, and that TNF‐α influences the progressive deterioration of diaphragm muscle in mdx mice. Muscle Nerve 28: 336–343, 2003

NMDA receptor-mediated modulation of ventilation in obese Zucker rats

BACKGROUND: Ventilation in response to hypoxia is reduced in some obese humans and is believed to represent part of the pathogenesis of obesity hypoventilation syndrome (OHS). Ventilation in response to hypoxic exposure is closely related to the release of excitatory neurotransmitters, in particular glutamate, acting specifically on N-methyl-D-aspartate (NMDA) receptors.OBJECTIVES: The aim of the present study was to investigate whether NMDA receptor-mediated mechanisms are responsible for the altered ventilatory response to sustained hypoxia observed in obese Zucker (Z) rats.SUBJECTS: Seven lean and seven 15-week-old obese male Z rats were studied.MEASUREMENTS: Ventilation ([Vdot ]E) at rest and during 30u2005min sustained hypoxic (10% O2) exposure was measured by the barometric method. [Vdot ]E was assessed following the blinded-random administration of equal volumes of either saline (vehicle) or dextromethorphan (DM, 10u2005mg/kg), a non-competitive glutamate NMDA receptor antagonist.RESULTS: DM had no effects on resting [Vdot ]E in both lean and obese rats during room air breathing. Lean rats treated with DM exhibited a significant (P<0.05) depression in [Vdot ]E, VT, and VT/TI during either the early (5u2005min) or the late phase (30u2005min) of ventilatory response to sustained hypoxia. In contrast, DM administration in obese rats did not change [Vdot ]E, VT, or VT/TI during the early phase of ventilatory response to hypoxia. During the late phase of ventilatory response to hypoxia. obese rats treated with DM exhibited a similar depression in [Vdot ]E and VT as observed in lean rats, but had no significant change in VT/TI during the 30u2005min hypoxic exposure.CONCLUSION: Our findings indicate that altered glutamatergic mechanisms acting on NMDA receptors are partially responsible for a blunted early phase of ventilatory response to hypoxia noted in obese rats and also contribute to their reduced neural respiratory drive.

Contractility of the ventilatory pump muscles

The ventilatory muscles are striated skeletal muscles, and their in situ function is governed by the same relationships that determine the contractile force of muscles in vitro. The ventilatory muscles, however, are functionally distinct from limb skeletal muscles in several aspects, the most notable being that the ventilatory muscles are the only skeletal muscles upon which life depends. Among the muscles that participate in ventilation, the diaphragm is closest to its optimal resting length at functional residual capacity (FRC) and has the greatest capacity for shortening and volume displacement, making it the primary muscle of inspiration. All inspiratory muscles shorten when the lung is inflated above FRC, but interactions among the various inspiratory muscles make for a wider range of high force output than could be achieved by any one muscle group acting in isolation. The velocity of inspiratory muscle shortening, especially diaphragmatic shortening, causes maximal dynamic inspiratory pressures to be substantially lower than maximal static pressures. This effect is especially pronounced during maximal voluntary ventilation, maximal exercise, and maximal inspiratory flow, volume maneuvers over the full vital capacity. During quiet breathing, the ventilatory muscles operate well below the limits of their neural activation and contractile performance. During intense activity, however, the diaphragmatic excursion approaches its limits over the entire vital capacity, and respiratory pressures may near their dynamic maximum. Because the system may operate near its available capacities during increased ventilatory demands, multiple strategies are available to compensate for deficits. For example, if the diaphragm is acutely shortened, it can still generate the required respiratory pressure if it receives more neural drive. Alternatively, other muscles can be recruited to take over for an impaired diaphragm. Thus, the whole system is highly versatile.