Diaphragm dysfunction in chronic obstructive pulmonary disease: a role for heparan sulphate?

Abstract

In the present study, phage display-derived antibodies were used to investigate the topology of glycosaminoglycan epitopes in the diaphragm of chronic obstructive pulmonary disease (COPD) and non-COPD patients. Furthermore, the potential physiological significance of changes in the occurrence of glycosaminoglycan epitopes in the diaphragm of COPD patients was studied by determining the overlap in epitope recognition of glycosaminoglycan antibodies and growth factors.Diaphragm cryosections from non-COPD (n55) and COPD patients (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I/II; n59) were incubated with antibodies directed against heparan sulphate, chondroitin sulphate and dermatan sulphate epitopes. Antibodies were visualised immunofluorescently. In addition, interference of antibody and growth factor binding with heparan sulphate epitopes was tested.Specific glycosaminoglycan epitopes showed increased expression in the diaphragm of COPD patients, whereas other epitopes were decreased or unaffected. Interestingly, the anti-heparan sulphate antibody HS4C3, which is directed against a downregulated epitope, interfered with the binding of hepatocyte growth factor. Three patients with the most severe airway obstruction also demonstrated interference of heparan sulphate antibody A04B08 with hepatocyte growth factor binding.Results indicate changes in glycosaminoglycan composition in the diaphragm of patients with chronic obstructive pulmonary disease. This may affect cellular physiology via alterations in growth factor handling and might be related to reduced levels of contractile protein in the diaphragm of these patients.

Respiratory muscle fiber remodeling in chronic hyperinflation: dysfunction or adaptation?

“…The largest exceptions to this are the work of Lewis et al (43), who showed reductions in in vitro specific force of Ͼ20%, and Huenks et al (32), who demonstrated reductions of ϳ14%. In human studies of isolated fibers from biopsy specimens, two groups, Levine et al (40) and Ottenheijm et al (64), have found significant reductions in specific force in individual costal diaphragm fibers (Table 2), an observation recently confirmed in another group of COPD patients by these authors (86 1, increase; 2, decrease; TLC, total lung capacity; FRC, functional residual capacity;…”

“…It has been proposed that the adaptations of the diaphragm in COPD demonstrate a kind of muscle dysfunction or impairment (62)(63)(64)84). This may be true, and findings such as loss of Ca 2ϩ sensitivity and atrophy certainly lead us in this direction.…”

“…Scott et al (79) showed overall reductions in median fiber area of all muscle cells in the diaphragm (ϳ14%), but did not evaluate individual categories of fiber. Doucet et al (18) found only small changes in fiber size in COPD patients, and Ottenheijm et al (64) found a small but insignificant increases in type I fiber CSA in mild COPD patients. Therefore, human type I fibers may undergo selective atrophy in patients with COPD, but it is not a universal finding and is probably more likely to be present in patients with severe disease (40).…”

A szív pozitív inotróp támogatása a miozin-aktivátor hatású omecamtiv mecarbil segítségével

“…Összességében, saját vizsgálati eredményeink cáfolják azt, hogy az OM egy szívizom-specifi kus miozin-aktivátor lenne, mivel jellegzetes hatásai némileg kisebb hatékonysággal, de lassú típusú vázizomrostokban is kialakultak. A vázizomros-tok Ca 2+ -érzékenyítése révén a jövőben az OM-et (és annak potenciálisan kifejlesztendő származékait) a vá-zizomzat krónikus elgyengülésével járó kórképekben is kipróbálhatják majd, mint alternatív terápiás eszközt (30,31). Jelenleg nem áll rendelkezésre olyan in vitro vagy in vivo tanulmány, amelyben az OM-hatásait vizsgálták volna légzési elégtelenségben.…”

Effect of Global Postural Re- Education Method on Pulmonary Function And Chest Excursion in Moderate Chronic Obstructive Pulmonary Disease Subjects

“…6 Loss of skeletal muscle mass in COPD leads to muscle weakness. 7 which impairs respiratory muscle function resulting in pulmonary hyperinflation, Barrel chest and geometry of chest wall is altered with hyperinflation leading to chronic reduction of the opposition zone of the diaphragm 9.10 .Hyperinflation change the diaphragm fiber arrangement and length which is an important determinant of force generating capacity 8 . Pulmonary hyperinflation can shorten diaphragm fiber sarcomere displacing it from its optimal length precipitating a decrease in the mechanical efficiency of the muscle 12 .…”