Mark F. Sands

Asthma in the elderly: Current understanding and future research needs—a report of a National Institute on Aging (NIA) workshop

Asthma in the elderly is underdiagnosed and undertreated, and there is a paucity of knowledge on the subject. The National Institute on Aging convened this workshop to identify what is known and what gaps in knowledge remain and suggest research directions needed to improve the understanding and care of asthma in the elderly. Asthma presenting at an advanced age often has similar clinical and physiologic consequences as seen with younger patients, but comorbid illnesses and the psychosocial effects of aging might affect the diagnosis, clinical presentation, and care of asthma in this population. At least 2 phenotypes exist among elderly patients with asthma; those with longstanding asthma have more severe airflow limitation and less complete reversibility than those with late-onset asthma. Many challenges exist in the recognition and treatment of asthma in the elderly. Furthermore, the pathophysiologic mechanisms of asthma in the elderly are likely to be different from those seen in young asthmatic patients, and these differences might influence the clinical course and outcomes of asthma in this population.

Tissue inhibitor of metalloproteinase-1 modulates allergic lung inflammation in murine asthma

Matrix metalloproteinases (MMPs) modulate development, inflammation, and repair in lungs. Tissue inhibitors of MMPs (TIMPs) interact with MMPs, controlling the intensity and nature of the response to injury. Absence of MMP-9, -2, and -8 activities is associated with altered lung inflammation during allergic sensitization. To test the hypothesis that the absence of TIMP-1 enhances allergic lung inflammation, airway hyperreactivity (AHR), and lung remodeling in asthma, we studied TIMP-1 null (TIMP-1 KO) mice and their WT controls using an ovalbumin (OVA) asthma model. TIMP-1 KO mice, compared to WT controls, developed an asthma phenotype characterized by AHR, pronounced cellular lung infiltrates, greater reduction in lung compliance, enhanced Th2 cytokine mRNA and protein expression, and altered collagen lung content associated with enhanced MMP-9 activity. Our findings support the hypothesis that TIMP-1 plays a protective role by preventing AHR and modulating inflammation, remodeling, and cytokine expression in an animal model of asthma.

Localization of Matrix Metalloproteinase (MMP)-9 in Lung Tissue of a Murine Model of Allergic Asthma

MMP-9 (gelatinase B) is recognized in chronic obstructive pulmonary disease (COPD) and now asthma as playing a central role in matrix degradation in injury, as well as contributing to the remodeling process. The increasing focus on MMP-9 in human and animal research supports the need for a reliable immunostain in lung tissue. However, MMP-9 immunostaining in murine systems is hampered by several factors. First, many of the anti-human antibodies do not readily cross-react with murine MMP-9 despite the high degree of conservation between human and murine MMP-9. Secondly, the availability of detailed protocols is limited. Lung MMP-9 immunostaining is further complicated by technical issues such as edge effect, availability of positive and negative controls, antigen retrieval, staining specificity, and the need to achieve a delicate balance of primary and secondary antibody concentrations, and colorimetric reagents which will allow visualization of specific cell expression in highly delicate lung tissue, while also demonstrating adequate uptake in (extra-pulmonary) tissue controls. We describe a detailed method for immunostaining MMP-9 in mouse lung paraffin-embedded tissue utilizing human ovary as a control since MMP-9 is known to be over-expressed in human ovarian carcinomas.

Ciprofloxacin eradicates respiratory tract bacteria more rapidly than cephalosporins in patients with nosocomial pneumonia

Patients with nosocomial pneumonia treated with either IV ciprofloxacin or IV third generation cephalosporins (cefmenoxime or ceftazidime) were evaluated to determine the length of treatment required to sterilise their respiratory tract cultures. The time required to eradicate the respiratory pathogens was determined using daily cultures oftracheal aspirate secretions. All patients were also assessed for clinical outcomes, and all patients had measurement of the minimum inhibitory concentration (MIC) of the presenting pathogen. A clinical scoring system was employed to correlate rate of pathogen eradication with rate of clinical improvement. All patients had measurements of serum concentrations of the respective antibiotic. HPLC assays were used. Serum concentrations were analysed using the computer program ADAPT II to determine pharmacokinetic parameters (AVC, Vd and clearance) for each patient. The primary pharmacokinetic-pharmacodynamic comparison parameter was the area under the inhibitory time curve (AUIC). This measure of overall activity is calculated as (24-hour AVC + MIC). AVIC values in the patients ranged from 6.0 to over 7,212 per 24 hours. These values correlated closely with time to eradication of pathogens (p < 0.001), regardless of which of the three antibiotics the patient received. AVIC values> 125 also were predictive of clinical cures. While over 75% of patients in each of the three drug treatment regimens eventually achieved negative tracheal aspirate cultures (p, NS), there was a striking difference in the time required to sterilise these cultures. Appropriate AVIC values for ciprofloxacin sterilised cultures in an average of 1.9 days, while both cephalosporins at similar AUIC values required over five days to achieve negative cultures. The clinical symptom scoring revealed that faster clinical cures were associated with more rapid bacterial eradication for ciprofloxacin. We conclude that the more rapid in-vitro killing which is characteristic of ciprofloxacin can translate directly into more rapid clearance of bacteria in the respiratory tract of patients. Prospective studies should be designed to sample the infection site more frequently, in order to provide additional validation of these outcomes.

Infections in Patients with Autoimmune Diseases

The relationship between autoimmunity and infections is complex and bi-directional. Infections have been associated with the induction of autoimmunity as well as protection from autoimmune diseases. Infectious agents may play both a causative and protective role in the pathogenesis of some autoimmune disorders like Sjogren’s syndrome. Infections are a common cause of morbidity and mortality in patients with systemic autoimmune diseases. Considerable evidence has emerged regarding the greater susceptibility of patients with autoimmune disorders to infections due to predisposition from autoimmunity itself as well as the use of immunosuppressive therapy.

Role of Galectin-3 in the pathophysiology underlying allergic lung inflammation in a tissue inhibitor of metalloproteinases 1 knockout model of murine asthma

Asthma is a chronic inflammatory respiratory disease characterized by airway inflammation, airway hyperresponsiveness and reversible airway obstruction. Understanding the mechanisms that underlie the various endotypes of asthma could lead to novel and more personalized therapies for individuals with asthma. Using a tissue inhibitor of metalloproteinases 1 (TIMP‐1) knockout murine allergic asthma model, we previously showed that TIMP‐1 deficiency results in an asthma phenotype, exhibiting airway hyperreactivity, enhanced eosinophilic inflammation and T helper type 2 cytokine gene and protein expression following sensitization with ovalbumin. In the current study, we compared the expression of Galectins and other key cytokines in a murine allergic asthma model using wild‐type and TIMP‐1 knockout mice. We also examined the effects of Galectin‐3 (Gal‐3) inhibition on a non‐T helper type 2 cytokine interleukin‐17 (IL‐17) to evaluate the relationship between Gal‐3 and the IL‐17 axis in allergic asthma. Our results showed a significant increase in Gal‐3, IL‐17 and transforming growth factor‐β1 gene expression in lung tissue isolated from an allergic asthma murine model using TIMP‐1 knockout. Gal‐3 gene and protein expression levels were also significantly higher in lung tissue from an allergic asthma murine model using TIMP‐1 knockout. Our data show that Gal‐3 may regulate the IL‐17 axis and play a pivotal role in the modulation of inflammation during experimental allergic asthma.