Airspace enlargement is a well-recognized pathological signature of respiratory aging 
. Whether this process recapitulates or incorporates known pathways of organismal aging is unknown. We sought to delineate the molecular profile of age-related airspace enlargement by performing a time course transcriptional survey of the aging DBA/2J lung throughout adult life. We found a distinct gene induction pattern punctuated by immunoglobulin production and cell cycle dysregulation which attended the onset of airspace enlargement. Whereas cell cycle changes have been linked to organismal aging, we show a novel role of oxidant-triggered matrix remodeling and dysregulated lymphocyte function in the aging lung.
Despite the fact that airspace enlargement is a known feature of the aged lung, whether the lesion develops from injury or simply reflects reduced matrix abundance in tissue is a subject of debate. Recent observations, including those reported here, support the former paradigm. The oxidant injury, elastase activation and cell death preceding the onset of airspace enlargement in our studies strongly implicate age-associated tissue stressors. Consistent with this paradigm, Sato reported that SMP30-deficient mice, a proposed model for the “senile lung”, not only develop accelerated age-associated airspace enlargement but also display increased oxidative stress, cell death and susceptibility to cigarette smoke induced pulmonary emphysema 
Several investigators have shown or postulated reduced immune function in aged persons and in murine models of aging 
. Alterations in immune responses with aging likely contribute to the increased susceptibility to infectious insults and malignancy in elderly persons. Unfortunately, no unifying pattern of changes has been reported in humans or rodent models. Defects in humoral immunity can accompany aging, manifest in both reduced specific antibody responses and enhanced nonspecific antibody production 
. Impaired function of hematopoietic stem cells in the aging bone marrow seems to result in both reduced production of naïve B-cells and marked restriction of the B-cell immune repertoire in a murine system 
. Elevated serum immunoglobulin levels and increased antibody-producing cells in the spleen and bone marrow have also been reported in aging mice 
. We found that the upregulation of immunoglobulin genes during aging-related airspace enlargement is accompanied by B-cell expansion, B-cell activation and enhanced synthesis and deposition of immunoglobulin complexes in the lungs of aging mice. B-cell activation is a feature of several chronic inflammatory conditions such as COPD (chronic obstructive pulmonary disease), rheumatoid arthritis and multiple sclerosis. An increased number of lymphoid follicles in the airway submucosa has been identified not only in mice exposed to cigarette smoke, but also in patients with advanced emphysema 
. Others have invoked a pathogenic contribution of parenchymal and airway lymphoid collections, possibly representing an exaggerated immune response triggered by microbial, matrix or tobacco smoke antigens 
. A recent study showed an increase in autoantibodies directed against both lung epithelial and endothelial determinants in the serum of patients with COPD 
. In our aging lung model, there is no exposure to known airspace insults like microbes or tobacco smoke; nonetheless, oxidative stress, elastase activation and epithelial cell death occur. Thus, the trigger for the elaboration of immunoglobulins in the aging lung may involve oxidative stress promoted matrix degradation, an established mechanism for aging-associated tissue remodeling 
. While no significant matrix turnover is evident by histochemical staining at the 12 month time point, our zymography data suggests that low-level turnover is present at 8 months and may be sufficient to drive the initiation of the immune response ().
We propose three possible mechanisms connecting the immune signature with the airspace lesion (summarized in ). First, the enhanced elastase activity in the absence of histologic evidence of tissue damage might generate matrix degradation products that are immunogenic. This is a proposed but imperfectly supported mechanism for emphysema 
. The critical omission in the theory is the identification of a consistently triggering matrix-derived antigen. A second possibility is that an alteration in immunosurveillance at midlife could create a permissive environment for an immune response to develop to a variety of stimuli. Since the lung is an organ that is constantly exposed to foreign antigens, any impairment in immune function can translate into dysregulated innate and adaptive responses to antigen and lung-specific pathology. However, immunomodulatory mechanisms may be sufficiently preserved that the dysregulated response is eventually arrested. By this view, the ongoing airspace enlargement, oxidative stress and cell death manifest a tissue-specific inability to repair/regenerate the airspace compartment and low grade inflammation as reflected by macrophage infiltration. This paradigm is quite similar to the progressive airspace and airway pathology observed after smoking cessation in persons with COPD/emphysema. A third possible mechanism is that a primary alteration in oxidant/antioxidant balance, conferred by midlife, results in the generation of neoantigens secondary to oxidation of resident proteins in the lung, an organ exquisitely susceptible to oxidant injury. Such neoantigens could trigger a local immune response and initiate the sequelae described above. Both of these mechanisms rely on a relatively preserved immunomodulatory axis. Consequently, an active direction of our lab is the dissection of these immunomodulatory pathways as they relate to lung aging.
The studies presented here demonstrate two intriguing findings. First, we show that aging associated airspace enlargement develops during middle age and that a contemporaneous innate and adaptive immune signature heralds its onset. This signature consists of exuberant immunoglobulin production, B-cell activation, local immunoglobulin deposition and macrophage infiltration. Second, we demonstrate that early aging-associated oxidative stress and elastase activation precedes overt inflammation, immunoglobulin deposition and airspace enlargement. We present a novel pathogenetic scheme for aging-associated airspace enlargement with presenescent oxidative stress triggering both canonical and noncanonical mechanisms of emphysema. These findings suggest that the crucial point of intervention for aging related lung dysfunction may be well before airspace disease is clinically apparent.