Without CFTR-mediated HCO3secretion, airway epithelia of newborns with cystic fibrosis (CF) produce an abnormally acidic airway surface liquid (ASL), and the decreased pH impairs respiratory host defenses. However, within a few months of birth, ASL pH increases to match that in non-CF airways. Although the physiological basis for the increase is unknown, this timecourse matches the development of inflammation in CF airways. To learn whether inflammation alters CF ASL pH, we treated CF epithelia with TNFα and IL-17, two inflammatory cytokines that are elevated in CF airways. TNFα+IL-17 markedly increased ASL pH by upregulating pendrin, an apical Cl -/HCO3exchanger. Moreover, when CF epithelia were exposed to TNFα+IL-17, clinically approved CFTR modulators further alkalinized ASL pH. As predicted by these results, in vivo data revealed a positive correlation between airway inflammation and CFTR modulator-induced improvement in lung function. These findings suggest that inflammation is a key regulator of HCO3secretion in CF airways. Thus, they explain earlier observations that ASL pH increases after birth and indicate that for similar levels of inflammation, the pH of CF ASL is abnormally acidic. These results also suggest that a non-cellautonomous mechanism, airway inflammation, is an important determinant of the response to CFTR modulators.

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The pH of airway surface liquid (ASL) is a key factor that determines respiratory host defense; ASL acidification impairs and alkalinization enhances key defense mechanisms. Under healthy conditions, airway epithelia secrete base (HCO3¯) and acid (H+) to control ASL pH (pHASL). Neutrophil-predominant inflammation is a hallmark of several airway diseases, and TNFα and IL-17 are key drivers. However, how these cytokines perturb pHASL regulation is uncertain. In primary cultures of differentiated human airway epithelia, TNFα decreased and IL-17 did not change pHASL. However, the combination (TNFα+IL-17) markedly increased pHASL by increasing HCO3¯ secretion. TNFα+IL-17 increased expression and function of two apical HCO3¯ transporters, CFTR anion channels and pendrin Cl-/HCO3- exchangers. Both were required for maximal alkalinization. TNFα+IL-17 induced pendrin expression primarily in secretory cells where it was co-expressed with CFTR. Interestingly, significant pendrin expression was not detected in CFTR-rich ionocytes. These results indicate that TNFα+IL-17 stimulate HCO3- secretion via CFTR and pendrin to alkalinize ASL, which may represent an important defense mechanism in inflamed airways.

Changing demographics have made aging and age-related chronic diseases an enormous and growing biomedical and societal challenge. The biological processes of aging may involve a role for the gut microbiota. Aspects of host physiology such as immune homeostasis and energy balance are profoundly influenced by the microbiota. Immune dysregulation characterizes old age and constitutes a major pathomechanism underlying frailty and age-associated chronic diseases. A growing body of literature implicates age-related perturbations in the gut microbial ecology as contributing to a global inflammatory state in the elderly. A better understanding of the nature and determinants of the host-microbe relationship in old age has the potential to translate into strategies that promote healthy aging and extend life span. This review summarizes our current understanding of the configuration of the age-related gut microbiota and its likely role in determining the immune phenotype in the elderly. It also highlights the specific components of the microbiota that can be targeted to modulate the age-related chronic inflammation.

BACKGROUND:Recent emphasis has been placed on methods to predict fl uid responsiveness, but the usefulness of using fl uid boluses to increase cardiac index in critically ill patients with ineff ective circulation or oliguria remains unclear.