100 Years Of Respiratory Medi... Health Article

Future Strategies

Current treatment of pneumonia is largely based on timely prescription of adequate antibiotic therapy. However, antimicrobial treatments are hampered by the ever-increasing problem of resistant strains, and the prospects for future antibiotics preparations are gradually slimming. Alternative strategies are therefore needed based on a better knowledge of microbial pathogenetic mechanisms and a more complete comprehension of host defense systems.

The complexity of the mechanisms and mediators involved in inflammation and infection is increasingly being unraveled, and the genetic regions controlling these factors have been partly elucidated. Soluble and membrane-based receptors have been identified that are capable of recognizing non-mammalian microbial motifs and mobilizing close to instantaneous inflammatory reactions towards infection. An increasing number of peptides exerting antimicrobial activity are being recognized in airway secretions, associated with chemokines, cytokines, proteinase inhibitors, and surfactant proteins.

Genetic polymorphisms in genes for important inflammatory molecules such as tumor necrosis factor, the interleukin-1 family, interleukin-10, and angiotensin converting enzyme, as well as molecules involved in innate immunity antigen recognition, such as the mannose-binding lectin, CD-14, and Toll-like receptors (TLRs), have been investigated as potential modifiers in the natural history of sepsis and pneumonia. ⁷⁵ Better knowledge of underlying genetic traits may help identify patients at greater risk of severe complications following infection. On the other hand, over-activation of innate immune responses may be associated with excessive inflammation and tissue damage such as may be observed in sepsis.

In the future it may be possible to modulate the innate immune response in order to downplay pathways leading to tissue inflammation while enhancing mechanisms involved in microbial elimination. Antimicrobial peptides (AMPs) present in airway surface fluid are effector molecules of the innate immunity with direct antimicrobial and mediator function. They provide an initial host defense mechanism that protects mucosal and dry epithelial surfaces of all multicellular organisms. Several diseases in humans and laboratory animals are characterized by impairment in the function of an AMP. ⁷⁶ AMPs qualify as prototypes of innovative drugs that might be used as antibiotics, antipolysaccharide drugs or modifiers of inflammation. Antibiotics based on these naturally occurring mammalian peptides might elicit fewer allergic reactions compared to conventional antibiotics. Synthetic analogs of AMPs may evolve into novel and independent classes of antibiotics. ⁷⁷

Recently identified mammalian TLRs are capable of distinguishing pathogen from self-components, triggering cytokine production, and expressing co-stimulatory molecules necessary for lymphocyte activation. Central to the signaling cascade triggered by TLRs is the activation of transcription factors such as nuclear factor κB (NF- κ B) and activator protein-1 (AP-1), key regulators of inflammatory and immune responses. ⁷⁸ Given their central role in activating and modulating host responses to infection, and acting as a bridge between innate and adaptive immunity, TLRs are being currently studied as potential therapeutic targets. Soluble forms of TLRs may be made to bind and neutralize natural ligands before they activate potent proinflammatory responses in the host. Alternatively, antibodies or molecules similar to natural ligands could be employed in order to bind with TLR extracellular or intracellular domains, though failing to activate intracellular signaling. This may result in inhibition of pro-inflammatory cascades initiated by TLRs, while retaining TLR-related protective responses. ⁷⁹

Hepatocyte growth factor (HGF) is a is a heterodimeric protein produced, among others, by lung fibroblasts and macrophages, that promotes proliferation of type II epithelial cells following lung injury, restoring alveolar and bronchial epithelial integrity. ⁸⁰ Recently, HGF levels have been tested in serum and exhaled breath condensate of patients with pneumonia and other non-respiratory conditions. ⁸¹ During the first days of the infections, pneumonia patients had higher HGF serum levels compared to controls, followed by a marked drop at days 4–7 that persisted up to 4–6 weeks. Conversely, exhaled breath HGF levels, were also higher than controls during the acute phase, but showed non-drop through all the observation period, suggesting that local production of this factor is active during pneumonia. Future studies will be needed to determine whether local inhalation of HGF may be considered ad an adjuvant treatment, particularly in severe or complicated pneumonia cases.

Related Articles

Pneumonia
From MDConsult Clinical Topic Tour , a patient information series

Overview of Pneumonia
From Cecil Textbook of Medicine , a medical textbook

Pneumonia
From Textbook of Primary Care Medicine , a medical textbook