Marvin Lesser

Pulmonary function survey in spinal cord injury: influences of smoking and level and completeness of injury.

Spirometry was performed on 165 subjects with spinal cord injury (84 with quadriplegia and 81 with paraplegia). Subjects were characterized by level of lesion as: high quadriplegia (HQ, C4 and above not requiring mechanical ventilation), low quadriplegia (LQ, C5–8), high paraplegia (HP, T1–7), and low paraplegia (LP, T8–L3). Thirty-nine subjects had complete motor lesions, and 126 had incomplete motor lesions. Nonsmokers (54 with quadriplegia and 53 with paraplegia) were defined as those who had never smoked or those who had stopped smoking for 1 year. Current smokers (28 with quadriplegia and 28 with paraplegia) were defined as those who currently smoked cigarettes, cigars, and/or pipe or those who had quit for ⩽1 year. We found by linear regression analysis that forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), peak expiratory flow (PEF), and maximal voluntary ventilation (MVV) were inversely correlated with the level of injury (i.e., the higher the level of injury, the lower the parameter). In the HQ group, those with complete injury had significantly lower pulmonary function parameters than those with incomplete lesions. In contrast, there were no significant differences in pulmonary function parameters between complete and incomplete lesions in subjects in the LQ, HP, and LP groups. In the LQ, HP, and LP groups, the FEV, and PEF were significantly lower in smokers than in nonsmokers. Thus, this study demonstrates the effects of completeness of injury and smoking on pulmonary function in a large group of subjects with spinal cord injury.

Self-reported prevalence of pulmonary symptoms in subjects with spinal cord injury

To determine the prevalence of respiratory symptoms in subjects with chronic spinal cord injury (SCI), 180 subjects completed a standard respiratory questionnaire modified for subjects with limited mobility. Subjects were categorized as high tetraplegia (HT:C5 and above not requiring mechanical ventilation), low tetraplegia (LT: C6 – 8), high paraplegia (HP: T1 – 7), or low paraplegia (LP: T8 – L3). Overall, 68% of subjects reported one or more respiratory symptom. Breathlessness, the most prevalent complaint, was associated with level of lesion: HT=73%, LT=58%, HP=43% and LP=29%, whereas complaints of cough, phlegm, cough and phlegm, and wheeze did not differ significantly among subjects in the four groups. Breathlessness occurred significantly more often in the group with HT during rest or following exposure to hot air or passive smoke. Awareness of phlegm or wheeze was reported with increased prevalence among subjects with tetraplegia who had complete injuries. Among subjects with tetraplegia, respiratory complaints did not differ significantly in current smokers, former smokers, and non-smokers, whereas among subjects with paraplegia, phlegm and wheeze were reported more frequently among current smokers.

TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis

Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-β1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-β1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-β1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-β1 variants or haplotypes. The −509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the −509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the −509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the −509C and codon 10T, implicated in lower levels of TGF-β1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-β1, although future studies will be needed to correlate TGF-β1 protein levels with known TGF-β1 genotypes and assess whether there is a shared mechanisms for TGF-β1 in these two granulomatous diseases.

Bronchodilatory effects of ipratropium bromide in patients with tetraplegia

Airway hyperresponsiveness was recently described in patients with chronic cervical spinal cord injury (tetraplegia). The response was attributed to unopposed cholinergic broncho-constrictor activity due to loss of sympathetic innervation of the airway. To determine if the administration of a cholinergic antagonist alters resting airway tone in these patients, ipratropium bromide (72 μg) was administered by aerosol to 25 tetraplegic patients. We found that 12 of 25 patients (48%) had significant improvement (defined as ≥ 12%) in forced expired volume in 1 s (FEV1) and/or forced vital capacity (FVC). A significant correlation between airway responsiveness and complaints of dyspnea at rest, completeness of injury (sensory), or smoking history was not found. These findings of improved airflow after the use of an anticholinergic bronchodilator agent provides further evidence that transection of the cervical cord results in unopposed parasympathetic activity and a resultant increase in resting airway tone.

Relationship of respiratory symptoms with smoking status and pulmonary function in chronic spinal cord injury.

Abstract Objective: The relationship of respiratory symptoms to pulmonary function parameters and smoking status was assessed in subjects with chronic (>1 year) spinal cord injury (SCI). Methods and Participants: As part of their annual physical examination, subjects were queried regarding respiratory symptoms and underwent pulmonary function studies. The 180 patients who successfully completed pulmonary function testing were evaluated, including 79 subjects with tetraplegia (56 nonsmokers and 23 smokers) and 101subjects with paraplegia (78 nonsmokers and 23 smokers). Findings: Logistic-regression analysis revealed the following independent predictors of breathlessness: level of injury (tetraplegia, paraplegia, odds ratio = 3.5, P < 0.0015), cough combined with phlegm and/or wheeze (CPWZ, odds ratio = 3.1, P < 0.015), total lung capacity percentage predicted (TLC < 60%, odds ratio = 3.9, P < 0.02), and expiratory reserve volume (ERV < 0.6 L, odds ratio = 2.5, P < 0.05). Independent predictors of CPWZ were current smoking (odds ratio = 3.3, P < 0.004), breathlessness (odds ratio = 2.9, P < 0.03), and forced expiratory volume in 1second (FEV1 < 60%, odds ratio = 3.2, P < 0.01). Conclusion: Altered respiratory mechanics associated with tetraplegia contribute to breathlessness, restrictive ventilatory impairment (low TLC%), and reduced expiratory muscle strength (low ERV). These factors apparently overshadow adverse effects caused by smoking. Conversely, smoking and reduction of airflow (low FEV1%) were predictive of CPWZ, symptoms commonly associated with cigarette use.

A sensitive procedure for determination of cathepsin D: activity in alveolar and peritoneal macrophages

SummarySeveral new synthetic substrates fulfilling the specificity requirements of cathepsin D were synthesized. One of these D-Phe-Ser(O-CH2-C6H5)-Phe-Phe-Ala-Ala-pAB (pAB = p-aminobenzoate) proved to be highly sensitive and convenient for measuring activity. Enzyme determination was carried out in a two-step reaction. In the first step the enzyme hydrolyzes the Phe-Phe bond of the substrate at pH 3.4. In the second step aminopeptidase M (EC 3.4.11.2) degrades one of the products Phe-Ala-Ala-pAB at pH 7 to 8 with the release of free pAB, which is then determined by a diazotization procedure. Activity can be measured in as little as 1 to 5 µg of macrophage protein. The activity of cathepsin D in rat alveolar macrophages was almost ten times higher than in resident peritoneal macrophages, and more than 25 times higher than in blood monocytes. The data indicate that transformation of blood monocytes into macrophages is associated with a much greater increase of cathepsin D activity in alveolar than peritoneal macrophages.

Inhibition of airway hyperreactivity by oxybutynin chloride in subjects with cervical spinal cord injury

Objective: To further investigate mechanisms of airway hyperreactivity among subjects with chronic cervical spinal cord injury (SCI), we assessed airway responsiveness to aerosolized methacholine and histamine in subjects receiving chronic oxybutynin chloride therapy, and compared the findings with those not receiving the agent. Methods: Twenty-five male subjects with cervical SCI participated in this study; 12 were maintained on oral oxybutynin chloride and 13 served as age-matched controls. Six of the 12 subjects receiving oxybutynin were challenged with aerosolized methacholine, and six with histamine; seven of the 13 control subjects were challenged with aerosolized methacholine and the remaining six with histamine. Results: All 13 control subjects and all six oxybutynin/histamine subjects exhibited a significant bronchoconstrictor response (PC20<8 mg/ml), whereas mean PC20 values for the oxybutynin/methacholine group were ⩾25 mg/ml. Conclusion: Our finding that the bronchoconstrictor effects of methacholine were blocked by oxybutynin chloride while those of histamine were not suggests that oxybutynin acts primarily through anticholinergic pathways rather than by causing generalized airway smooth muscle relaxation.

Cathepsin B and D activity in stimulated peritoneal macrophages

SummaryHighly sensitive and specific synthetic substrates were used to quantitate cathepsin B and D activity in peritoneal macrophages in response to stimulation in vivo with mineral oil and thioglycollate. After intraperitoneal instillation of mineral oil the activity of cathepsin B increased significantly (to 15 300 units/mg protein versus 7 340 in saline controls), reaching values approaching those found in alveolar macrophages (18 400 units/mg protein). Significantly greater stimulation of enzyme activity was obtained after intraperitoneal instillation of thioglycollate (23 600 units/mg protein). Cathepsin D activity also increased significantly after both mineral oil and thioglycollate. However, the increase was moderate (from 806 to about 1 200 units/mg protein), remaining still more than six times lower-than in alveolar macrophages. The data are the first to demonstrate that cathepsin B activity can be stimulated in vivo in peritoneal macrophages by instillation of agents that induce acute inflammation. They also point to a differential control of expression of cathepsin B and D activity in both peritoneal and alveolar macrophages in spite of the common lysosomal origin of the two enzymes.

Effects of GABA-B agonist baclofen on bronchial hyperreactivity to inhaled histamine in subjects with cervical spinal cord injury.

Abstract. Bronchial provocation studies performed in our research center have consistently demonstrated airway hyperresponsiveness to both inhaled methacholine and histamine in subjects with chronic cervical spinal cord injury (SCI). More recently, we reported that the airways of such subjects maintained on chronic baclofen (γ-aminobutyric acid) therapy were not hyperreactive to inhaled methacholine. In this study we determined whether baclofen also blocks the effects of the bronchoprovocative agent histamine in subjects with cervical SCI. Twenty-four male subjects with cervical SCI participated in this study; 14 were maintained on oral baclofen, and 10 served as age-matched controls. The subjects were challenged with increasing concentrations of aerosolized histamine until either a 20% fall in forced expiratory volume in 1 s (FEV1) from baseline (defined as PC20) was observed, or a maximum of 25 mg/ml histamine was administered. We found that 11 of the 14 baclofen subjects (78.5%) and 8 of the 10 control subjects (80%) responded (PC20 < 8 mg/ml) to the histamine challenge. Mean PC20 values among responders in the baclofen (PC20= 2.91 ± 2.3) and control (PC20= 2.18 ± 1.9) groups did not differ significantly. Because histamine acts directly on histamine receptors and indirectly on cholinergic pathways, our findings that baclofen blocks bronchoconstriction due to inhaled methacholine, but not that due to histamine, suggests that hyperresponsiveness in subjects with cervical SCI may be secondary to nonspecific airway hyperreactivity.

EFFECTS OF PEPTIDASE INHIBITORS ON BRADYKININ-INDUCED BRONCHOCONSTRICTION IN THE RAT

Objectives of this study were to determine if aerosolized bradykinin causes bronchoconstriction in anesthetized, mechanically ventilated rats, and if pretreatment with enalaprilat, an inhibitor of angiotensin-converting enzyme (ACE), or phosphoramidon, an inhibitor of endopeptidase 24.11 (EP 24.11), alters the response. We found that aerosolized bradykinin elicited a reproducible bronchoconstrictor response that was significantly amplified by pretreatment with aerosolized enalaprilat or phosphoramidon. Neither inhibitor alone affected airway tone or caused nonspecific airway hyperreactivity. These findings indicate that both ACE and EP 24.11 contribute to bradykinin degradation in rat airways.