Combined effects of intermittent hyperoxia and intermittent hypercapnic hypoxia on respiratory control in neonatal rats.

Chronic exposure to intermittent hyperoxia causes abnormal carotid body development and attenuates the hypoxic ventilatory response (HVR) in neonatal rats. We hypothesized that concurrent exposure to intermittent hypercapnic hypoxia would influence this plasticity. Newborn rats were exposed to alternating bouts of hypercapnic hypoxia (10% O2/6% CO2) and hyperoxia (30-40% O2) (5 cycles h-1, 24 h d-1) through 13-14 days of age; the experiment was run twice, once in a background of 21% O2 and once in a background of 30% O2 (i.e., "relative hyperoxia"). Hyperoxia had only small effects on carotid body development when combined with intermittent hypercapnic hypoxia: the carotid chemoafferent response to hypoxia was reduced, but this did not affect the HVR. In contrast, sustained exposure to 30% O2 reduced carotid chemoafferent activity and carotid body size which resulted in a blunted HVR. When given alone, chronic intermittent hypercapnic hypoxia increased carotid body size and reduced the hypercapnic ventilatory response but did not affect the HVR. Overall, it appears that intermittent hypercapnic hypoxia counteracted the effects of hyperoxia on the carotid body and prevented developmental plasticity of the HVR.

RIPK1-dependent apoptosis bypasses pathogen blockade of innate signaling to promote immune defense.

Many pathogens deliver virulence factors or effectors into host cells in order to evade host defenses and establish infection. Although such effector proteins disrupt critical cellular signaling pathways, they also trigger specific antipathogen responses, a process termed "effector-triggered immunity." The Gram-negative bacterial pathogen Yersinia inactivates critical proteins of the NF-κB and MAPK signaling cascade, thereby blocking inflammatory cytokine production but also inducing apoptosis. Yersinia-induced apoptosis requires the kinase activity of receptor-interacting protein kinase 1 (RIPK1), a key regulator of cell death, NF-κB, and MAPK signaling. Through the targeted disruption of RIPK1 kinase activity, which selectively disrupts RIPK1-dependent cell death, we now reveal that Yersinia-induced apoptosis is critical for host survival, containment of bacteria in granulomas, and control of bacterial burdens in vivo. We demonstrate that this apoptotic response provides a cell-extrinsic signal that promotes optimal innate immune cytokine production and antibacterial defense, demonstrating a novel role for RIPK1 kinase-induced apoptosis in mediating effector-triggered immunity to circumvent pathogen inhibition of immune signaling.