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Age-dependent alterations in the inflammatory response to pulmonary challenge

Significance Statement 

Changes in pulmonary physiology, pathology, and function are common in older populations, and lead to altered responses and increased morbidity and mortality associated with lung infections.  However, in many respects, the reasons for the altered susceptibility remain unclear.  Our previous studies have revealed that age influences early changes (6hrs after pulmonary challenge) in lung water and oxygen saturation (Lee et al Shock  2013, 40:Suppl 1, 27), and temperature control, hemodynamics and myocardial proteasome activity (Linge et al  Exp Lung Res  2015, 41:4, 216-227). Understanding age-related changes in the immune response within the pulmonary compartment and its impact on lung host defense and systemic responses, is of critical importance for developing effective therapeutic strategies for the treatment of the older patient. The current study highlights age-related changes and the possible interactions between inflammatory (MIF) and metabolic pathways (thyroxine) that are not immediately obvious (Al-Abed et al  PNAS 2011, 108:20, 8224–8227).  It also underlines the importance of using age-appropriate models for studying clinical conditions.

The research team brought together individuals  with a variety of ethnic backgrounds (Sweden, Pakistan, China, S. Korea and England) and specialties/interests (host response, internal medicine, analytical chemistry, pulmonary critical care, bio/clinical chemistry). A diverse group can result  in different approaches to a single  problem, and differences in interpretation of data achieved. This has led to a series of interesting studies and publications (including the current manuscript) that have revealed some aspects of disease pathogenesis that have not previously been considered.

Journal Reference  

Immunol Res. 2015 Aug 29. 

Linge HM, Ochani K, Lin K, Lee JY, Miller EJ.

Center for Heart and Lung Research, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.

Abstract

The aging lung is increasingly susceptible to infectious disease. Changes in pulmonary physiology and function are common in older populations, and in those older than 60 years, pneumonia is the major cause of infectious death. Understanding age-related changes in the innate and adaptive immune systems, and how they affect both pulmonary and systemic responses to pulmonary challenge are critical to the development of novel therapeutic strategies for the treatment of the elderly patient. In this observational study, we examined age-associated differences in inflammatory responses to pulmonary challenge with cell wall components from Gram-positive bacteria. Thus, male Sprague-Dawley rats, aged 6 months or greater than 18 months (approximating humans of 20 and 55-65 years), were challenged, intratracheally, with lipoteichoic acid and peptidoglycan. Cellular and cytokine evaluations were performed on both bronchoalveolar lavage fluid (BAL) and plasma, 24 h post-challenge. The plasma concentration of free thyroxine, a marker of severity in non-thyroidal illness, was also evaluated. The older animals had an increased chemotactic gradient in favor of the airspaces, which was associated with a greater accumulation of neutrophils and protein. Furthermore, macrophage migration inhibitory factor (MIF), an inflammatory mediator and putative biomarker in acute lung injury, was increased in both the plasma and BAL of the older, but not young animals. Conversely, plasma free thyroxine, a natural inhibitor of MIF, was decreased in the older animals. These findings identify age-associated inflammatory/metabolic changes following pulmonary challenge that it may be possible to manipulate to improve outcome in the older, critically ill patient.

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Age-dependent alterations in the inflammatory response to pulmonary challenge. Global Medical Discovery