NIEHS - Lung Microbiome Promotes Emphysema by Activating Lung Innate Immunity

Lung Microbiome Promotes Emphysema by Activating Lung Innate Immunity
Chronic obstructive pulmonary disease (COPD) is increasing worldwide and soon will surpass the global burden of infectious diseases as a cause of morbidity and mortality worldwide. Despite the enormous clinical burden of COPD, specific treatments are limited. However, it is well-understood that COPD is a disease that occurs with age, suggesting that aging and senescence promote the development of COPD. As the proportion of Americans over age 65 will reach 19% of the population by 2030, there is an imperative to better understand the fundamental mechanisms of COPD in the context of aging.

Activation of the innate immune system prevents lung oxidative stress, senescence and COPD (1-3). Deficiency in TLR4, an innate immune receptor recognizing bacterial lipopolysaccharide, is associated with emphysema in mice (1). Microbiome also promotes epithelial homeostasis via activation of TLR4 and its downstream adapter molecule MyD88 in the gut (4). Thus, in our original experiment we were hypothesizing that GF mice will have increased emphysema (Projects CS027798, CS026653).

Surprisingly, we found the opposite: GF mice were protected from age-related emphysema, compared to SPF mice (Figure 1). A similar phenotype was observed in TLR5 deficient SPF mice. Interestingly, we also found that TLR5 deficiency was associated with lung fibrosis in a substantial subgroup of aged mice. This leads us to hypothesize that the lung microbiome may promote age-related emphysema by inducing inflammation through TLR5, and that absence of innate immune activation may lead to dysbiosis which leads to epithelial injury and lung fibrosis.

We propose the following Specific Aims:

a) To confirm whether GF mice are protected from age-associated emphysema compared to genetically identical mice raised in SPF conditions.
b) To determine whether GF mice are protected from inflammaging compared to similarly aged SPF-raised mice.
c) To determine whether GF conditions prevent the development of spontaneous lung fibrosis associated with TLR5 deficiency.

We can pursue these specific Aims as follows:
1. To determine whether GF mice develop increased senescence and emphysema with age, 10 male and 10 female C57BL/6J mice (commercially available to ship to the GF facility) will be allowed to age up to 16 months in GF conditions. Control C57BL/6J mice will be maintained in SPF conditions. At the determined time, mice will be shipped to the NIEHS where they will undergo a battery of tests to determine lung physiology, immunology senescence and histology analysis. To maximize scientific output, NIEHS colleagues who are interested in other organ systems (liver, intestine, brain) will have access to these organs as well.
2. To determine whether TLR5 deficient mice are protected from fibrosis in GF conditions, TLR5 deficient mice will be bred and aged in the GF facility. At the determined time, mice will be shipped to the NIEHS where they will undergo a battery of tests to determine lung physiology, immunology senescence and histology analysis and compared to similarly aged SPF mice at the NIEHS.

Grant Number: 75N91019D00024-0-759102500016-22
NIH Institute/Center: NIH
Principal Investigator: lynn briscoe